piperidines and Memory-Disorders

Prevention of cognitive impairment and dementia is an important public health goal. Epidemiological evidence shows a relationship between cognitive impairment and Type 2 diabetes mellitus. The risk of dementia increases with duration of disease. This updated systematic review investigated the effect on cognitive function of the type of treatment and level of metabolic control in people with Type 2 diabetes.. To assess the effects of different strategies for managing Type 2 diabetes mellitus on cognitive function and the incidence of dementia.. We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG)), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL and LILACS on 15 October 2016. ALOIS contains records from all major health care databases, (CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many trials' registers and grey literature sources.. We included randomised controlled trials (RCTs) which compared two or more different treatments for Type 2 diabetes mellitus and in which cognitive function was measured at baseline and after treatment.. Two review authors independently extracted data and assessed the quality of the included RCTs. We pooled data for comparable trials and estimated the effects of treatment by using risk ratios (RRs) and mean differences (MDs), according to the nature of the outcome. We assessed the quality of the evidence using GRADE methods.. We identified seven eligible studies but only four provided data we could include in efficacy analyses. Two of these studies compared intensive versus standard glycaemic control and two compared different pharmacological treatments. All studies were at unclear risk of bias in at least two domains and one large study was at high risk of performance and detection bias.(a) Two studies with 13,934 participants at high cardiovascular risk provided efficacy data on intensive versus standard glycaemic control. A third study with 1791 participants provided additional data on hypoglycaemic episodes and mortality. There is probably no difference between treatment groups in the number of participants who decline by at least 3 points on the Mini-Mental State Examination (MMSE) over five years (RR 0.98, 95% CI 0.88 to 1.08; 1 study; n = 11,140; moderate-quality evidence); and there may also be little or no difference in the incidence of dementia (RR 1.27, 95% CI 0.87 to 1.85; 1 study; n = 11,140; low-quality evidence). From another study, there was probably little or no difference in MMSE score after 40 months (MD -0.01, 95% CI -0.18 to 0.16; 1 study; n = 2794; moderate quality evidence). Participants exposed to the intensive glycaemic control strategy probably experience more episodes of severe hypoglycaemia than those who have standard treatment (RR 2.18, 95% CI 1.52 to 3.14; 2 studies; n = 12,827; moderate-quality evidence). The evidence from these trials suggests that the intensity of glycaemic control may have little or no effect on all-cause mortality (RR 0.99, 95% CI 0.87 to 1.13; 3 studies; n = 15,888; low-quality evidence).(b) One study with 156 participants compared glibenclamide (glyburide) with repaglinide. There may be a small advantage of glibenclamide on global cognitive function measured with the MMSE after 12 months (MD -0.90, 95% CI -1.68 to -0.12; low-quality evidence). No data were reported on the incidence of dementia, hypoglycaemic events or all-cause mortality.(c) One study with 145 participants compared rosiglitazone plus metformin to glibenclamide (glyburide) plus metformin over 24 weeks. It reported only on cognitive subdomains and not on global cognitive function, incidence of MCI or dementia, hypoglycaemic events or all causes of mortality.. We found no good evidence that any specific treatment or treatment strategy for Type 2 diabetes can prevent or delay cognitive impairment. The best available evidence related to the comparison of intensive with standard glycaemic control strategies. Here there was moderate-quality evidence that the strategies do not differ in their effect on global cognitive functioning over 40 to 60 months.

Topics: Carbamates; Cause of Death; Cognition Disorders; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Memory Disorders; Metformin; Piperidines; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones

Topics: Adult; Donepezil; Ginkgo biloba; Humans; Indans; Memantine; Memory Disorders; Multiple Sclerosis; Neuroprotective Agents; Nootropic Agents; Phytotherapy; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cyclic AMP Response Element-Binding Protein; Donepezil; Drug Discovery; Extracellular Signal-Regulated MAP Kinases; Galantamine; Hippocampus; Humans; Indans; Long-Term Potentiation; Memantine; Memory; Memory Disorders; Molecular Targeted Therapy; Nootropic Agents; Phenylcarbamates; Piperidines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Rivastigmine; Synaptic Transmission

This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent.. To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS.. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings.. All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater.. Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation.. We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups.. We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

Topics: Adult; Donepezil; Ginkgo biloba; Humans; Indans; Memantine; Memory Disorders; Middle Aged; Multiple Sclerosis; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Memory disorder is one of the most frequent cognitive impairment and has a great negative impact on the quality of life in patients with multiple sclerosis (MS). A few pharmacologic agents appear to be effective to memory disorder in patients with MS in some existing randomised controlled trials.. To assess the absolute and comparative efficacy, tolerability and safety of pharmacologic treatments for memory disorder in adult patients with MS.. We searched the Cochrane Multiple Sclerosis Group's Trials Register (17 January 2011), PsycINFO (January 1980 - April Week 4 2011) and CBMdisc (January 1978 - 6 April 2011), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings.. All double-blind, randomized controlled parallel trials on pharmacologic treatment versus placebo treatment or no treatment or one or more pharmacologic treatments, without restrictions regarding dose, route of administration and frequency, administration duration≥12 weeks for memory disorder in adult patients with MS who display at least mild memory impairment at 0.5 standard deviations below age -and-sex-based normative data on a validated memory scale. Adequately randomized or quasi-randomized trials were included.. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation.. Four RCTs involving adult patients with all the types of MS and at least mild memory impairment were included, evaluating donepezil, Ginkgo biloba (GB), memantine and rivastigmine respectively vs placebo in treating memory disorder in MS.There were no serious adverse events in intervention groups.The quality of the included studies was overall low, some of important variables were not matched between groups at baseline, the samples of subjects were relatively small and the follow-up was short. Three RCTs which evaluate GB, memantine, rivastigmine respectively vs placebo are currently ongoing.. Until the results of ongoing studies are available, there is no convincing evidence to support pharmacologic intervention as an effective treatment for memory disorder in MS patients. However, donepezil, Ginkgo biloba, memantine and rivastigmine resulted to be safe and well tolerated as adverse events such as nausea, diarrhea, somnolence, and constipation were not frequent,  while no serious adverse effects were reported. Future high quality randomised controlled trials are needed.

Topics: Adult; Donepezil; Ginkgo biloba; Humans; Indans; Memantine; Memory Disorders; Middle Aged; Multiple Sclerosis; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Topics: Aged; Cognition; Depression; Donepezil; Geriatric Assessment; Ginkgo biloba; Humans; Indans; Memory Disorders; Nootropic Agents; Phytotherapy; Piperidines; Polypharmacy; Thinking

This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

Topics: Alzheimer Disease; Animals; Attention; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Brain Injuries; Donepezil; Down Syndrome; Humans; Indans; Learning Disabilities; Memory Disorders; Mental Recall; Nootropic Agents; Piperidines; Schizophrenia; Treatment Outcome

Problems with memory which do not meet the diagnostic criteria for dementia, usually called mild cognitive impairment (MCI), can be the first sign of an impending dementia, particularly Alzheimer's disease (AD). There is no consensus on a definition or diagnostic criteria for MCI, and MCI remains a vague term and those so described are a heterogeneous population, consisting of people who may rapidly progress to dementia but also of people with stable cognitive deficits and some who may actually improve. Treatment in the very earliest stages of AD may delay progression to AD. Donepezil (Aricept, E2020), a cholinesterase inhibitor, has been shown to benefit all severities of AD including mild and it would be reasonable to investigate its efficacy for those with MCI.. To assess the effects of donepezil in people with mild cognitive impairment but no diagnosis of dementia.. The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 6 January 2006. This register contains records from major health care databases like CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO and many ongoing trial databases and is updated regularly.. All double blind, randomized trials in which treatment with donepezil was compared with placebo for patients with mild cognitive impairment.. Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated.. The two included studies, with a total of 782 patients, all with a MMSE greater than 23 points, identified similar patients for inclusion, but were quite different with respect to design and objective. Pooling results in a meta-analysis was not possible. In the first study the 13-item ADAS-Cog showed benefit associated with 10 mg/day donepezil compared with placebo at 24 weeks (MD 1.90, 95% CI 0.51 to 3.29, p=0.007), but four other measures of cognitive function did not. The analysis of withdrawals before the end of treatment at 24 weeks, withdrawals due to an adverse event, and numbers experiencing an adverse event, showed a significant difference between the donepezil group and the placebo group in favour of placebo, (43/133 donepezil 23/137 placebo, OR 2.37, 95% CI 1.33 to 4.22, p=0.003), (29/133 donepezil 10/137 placebo, OR 3.54, 95% CI 1.65 to 7.60, p=0.001), (116/133 donepezil, 100/137 placebo, OR 2.52 95% CI 1.34 to 4.76, p=0.004). Various adverse effects were recorded, and several types of event, diarrhoea, nausea, vomiting, leg cramps and abnormal dreams, were reported more frequently in the donepezil group compared with the placebo. In the second study there was a significant difference between the number of patients diagnosed with AD or another dementia between the donepezil group and the placebo group in favour of donepezil after one year of treatment (16/253 donepezil 38/259 placebo) (OR 0.39, 95% CI 0.21 to 0.72, p=0.003), but no difference after 3 years of treatment (63/253 donepezil 73/259 placebo) (OR 0.84, 95% CI 0.57 to 1.25, p=0.4).. There are two included studies. One study demonstrated a modest treatment effect in cognitive function as assessed by ADAS-Cog13 but not for other outcomes assessing different domains of cognitive function. Donepezil was associated with significantly more adverse effects compared with placebo, mostly gastrointestinal. From the second study, there is no evidence that donepezil delays the onset of AD. There is no evidence to support the use of donepezil for patients with MCI. The putative benefits are minor, short lived and associated with significant side effects.

Topics: Donepezil; Humans; Indans; Memory Disorders; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

M1 muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer's disease (AD): beta-amyloid (Abeta) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 muscarinic agonists AF102B (Cevimeline, EVOXAC trade mark : prescribed for Sjøgren's syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (alpha-APP), (via alpha-secretase activation), to decreased Abeta (via gamma-secretase inhibition), and to inhibition of Abeta- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation, with a high safety margin, following po administration. Notably, in mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm, in reversal learning. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Abeta in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 agonists can decrease brain Abeta, owing to a novel and dual complementary effect (e.g., inhibition of gamma-secretase and activation of alpha-secretase). Remarkably, although M1 agonists can decrease CSF Abeta in AD patients, an increased AD-type pathology in Parkinson's disease was recently been associated with chronic antimuscarinic treatment. In another aspect, these agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., beta- or gamma-secretase inhibitors, vaccines against Abeta, statins, and inhibitors of tau hyperphosphorylation).

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cell Death; Disease Models, Animal; Down-Regulation; Humans; Memory Disorders; Mice; Muscarinic Agonists; Oxidative Stress; Piperidines; Quinuclidines; Receptor, Muscarinic M1; Spiro Compounds; tau Proteins; Thiazoles; Thiophenes

Many neuropsychiatric disorders affect memory. Brain regions important in the neuroanatomic substrate of memory include the hippocampus, and sections of the frontal, temporal, and parietal cortices and the thalamus. Acetylcholine and many other neurotransmitters and neuromodulators including dopamine, glutamate, GABA, the catecholamines, and estrogen modulate cognitive function. Treatment approaches to memory loss typically use Alzheimer's dementia as the template, and are discussed in this report.

Topics: Aging; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cholinesterase Inhibitors; Dementia; Donepezil; Estrogen Replacement Therapy; Humans; Indans; Memory Disorders; Nootropic Agents; Piperidines; Premenopause; Randomized Controlled Trials as Topic; Tacrine

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Ethics, Medical; Female; Humans; Indans; Male; Memory Disorders; Personal Autonomy; Personhood; Physician-Patient Relations; Piperidines; Quality of Life; Risk Assessment; Self Concept; Truth Disclosure; Value of Life; Withholding Treatment

A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H. Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H. The treatment of H. These results highlight a novel interaction between the central histamine signaling and memory engrams.

Topics: Adult; Animals; Betahistine; Cognition; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Memory Disorders; Mental Recall; Mice; Mice, Inbred C57BL; Object Attachment; Perirhinal Cortex; Piperidines; Stochastic Processes; Young Adult

Use of cross-species neuropsychological paradigms such as visual-spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities.. This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, "process-based" computerized measure of visual-spatial PAL.. In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual-spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual-spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil.. Acute scopolamine challenge can produce large and robust deficits in visual-spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual-spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Executive Function; Humans; Indans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Paired-Associate Learning; Piperidines; Scopolamine; Time Factors; Young Adult

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.

Topics: Analysis of Variance; Animals; Atrophy; Brain; Caloric Restriction; Case-Control Studies; Cognition Disorders; Cyclin-Dependent Kinase 5; Disease Models, Animal; Double-Blind Method; Excitatory Postsynaptic Potentials; Female; Green Fluorescent Proteins; Immunoprecipitation; In Vitro Techniques; Long-Term Potentiation; Male; Memory Disorders; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphopyruvate Hydratase; Phosphotransferases; Piperidines; Silver Staining; Sirtuin 1; Synapses; Thiazoles; Tumor Suppressor Protein p53; Vitamin E

Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimer's disease (pAD).. Using functional magnetic resonance imaging, 31 healthy participants were studied. The response in 18 MCI and 18 pAD patients was then determined, and compared to 18 matched healthy controls. Subjects heard factual sentences, and subsequent retrieval performance indicated successful registration and episodic encoding.. The healthy subjects demonstrated that suppression of auditory cortical responses was related to greater success in encoding heard sentences; and that this was also associated with greater activity in the semantic system. In contrast, there was reduced auditory cortical suppression in patients with MCI, and absence of suppression in pAD. Administration of a central cholinesterase inhibitor (ChI) partially restored the suppression in patients with pAD, and this was associated with an improvement in verbal memory.. Verbal episodic memory impairment in AD is associated with altered auditory cortical function, reversible with a ChI. Although these results may indicate the direct influence of pathology in auditory cortex, they are also likely to indicate a partially reversible impairment of feedback from neocortical systems responsible for sustained attention and semantic processing.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Auditory Cortex; Auditory Perceptual Disorders; Cognitive Dysfunction; Donepezil; Female; Humans; Indans; Limbic System; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Mental Recall; Middle Aged; Nootropic Agents; Piperidines; Verbal Learning; Young Adult

The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).. Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.. A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.. Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.. This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Piperidines; Treatment Outcome; Verbal Learning; Young Adult

Emotional processing measures are sensitive to acute administration of clinically useful antidepressant drugs. We wished to test the hypothesis that these models would also be able to detect agents likely to cause depression as an adverse effect. The anti-obesity drug and cannabinoid type 1 receptor antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use.. Thirty healthy adult volunteers were randomly assigned to receive a single dose of rimonabant (20 mg) or lactose placebo in a double-blind, between-groups design. Three hours after medication administration, subjects undertook an emotional processing test battery including facial emotion recognition, emotional word attentional dot probe, self-relevant word classification, emotional and declarative memory and the emotion-potentiated acoustic startle response. Subjective state was assessed via self-report measures.. A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing.. These results suggest that a single dose of rimonabant decreases positive emotional memory in the absence of changes in subjective state. Further studies are required to examine whether rimonabant might produce a wider range of negative emotional biases with repeated treatment.

Topics: Acoustic Stimulation; Adolescent; Adult; Analysis of Variance; Dose-Response Relationship, Drug; Double-Blind Method; Emotions; Female; Humans; Male; Memory; Memory Disorders; Neuropsychological Tests; Pain Measurement; Pattern Recognition, Visual; Personality Inventory; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology; Reflex, Startle; Rimonabant; Time Factors; Verbal Learning; Young Adult

Scopolamine-induced deficits in cognitive and motor processes have been widely demonstrated in animals and humans, although the role of acetylcholine in working memory is not as well understood. This study examined the role of acetylcholine neurotransmission in visuospatial short term and working memory using the Groton Maze Learning Test (GMLT). The GMLT is a computerized hidden maze learning test that yields measures of component cognitive processes such as spatial memory, working memory, and visuomotor function, as well as their integration in trial-and-error problem solving. Healthy older adults were administered scopolamine (0.3 mg subcutaneous), the acetlycholinesterase inhibitor donepezil (5 mg oral), scopolamine with donepezil, or placebo. Compared to placebo, low-dose scopolamine led to performance deficits on all measures of the GMLT. The greatest scopolamine-induced deficits were observed in errors reflecting working memory processes (e.g., perseverative errors d=-2.98, and rule-break errors d=-2.49) and these impairments remained robust when statistical models accounted for scopolamine-related slowing in visuomotor speed. Co-administration of donepezil partially ameliorated scopolamine-related impairments and this effect was greatest for measures of working memory than short-term memory. By itself, donepezil was associated with a small improvement in visuomotor function. These results suggest that scopolamine disrupts processes required for rule maintenance and performance monitoring, in combination with visuomotor slowing and sequential location learning.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Geriatric Assessment; Humans; Indans; Linear Models; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Piperidines; Scopolamine; Spatial Behavior

To determine if donepezil, an acetylcholinesterase (AChE) inhibitor, improved the assimilation of cognitive training by older adults with memory complaints, we gave 168 nondemented, community-dwelling volunteers with memory complaints either 5 mg of donepezil (Aricept) or placebo daily for 6 weeks in a randomized, double-blind, placebo-controlled trial. The dosage rose to 10 mg daily for another 6 weeks before a 2-week course of cognitive training and was maintained for the remainder of a year. Cognitive training improved performance; donepezil was well tolerated. However, there were no significant benefits of donepezil compared with placebo. An additional dose-ranging study with a starting dose of 5 mg a day suggests that the high dose was not the reason. Physiological tolerance may occur with chronic donepezil treatment and may increase AChE levels; this may be why short-term studies have shown the benefit of AChE inhibitor use in nondemented participants whereas chronic use has failed to enhance cognition.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Combined Modality Therapy; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Piperidines; Psychotherapy

This paper reviews the key lessons learned from the first published short-term, placebo-controlled trial of a cholinesterase inhibitor for treatment of mild cognitive impairment (MCI).. The study was a 24-week placebo-controlled trial designed to evaluate the efficacy and safety of donepezil HCl (donepezil) in the treatment of cognitive impairment in subjects with MCI. Primary outcome measures were the NYU Paragraphs Test and the ADCS Clinicians Global-Impression of Change in the intent-to-treat last-observation-carried-forward group.. There was no benefit of donepezil treatment on primary outcome measures (NYU Paragraphs and ADCS CGI-C) in the ITT-LOCF group but positive findings were seen on NYU Paragraphs in the fully evaluable group and in certain secondary outcome measures across both groups.. The results highlight the need for the use of primary cognitive and functional measures that are reliable and sensitive to change in patients with MCI. Measures of episodic memory, psychomotor speed and complex attention were most sensitive in this study. Functional rating scales are needed that measure change in individual subjects' key areas of functional deficit, which typically involve executive aspects of instrumental ADLs. Tolerability can be increased by use of flexible dosing and efficacy is likely to be enhanced by increasing the length of the trial from six to 12 months and by enriching the sample with subjects more likely to decline during the trial.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; History, 20th Century; Humans; Indans; Memory Disorders; Neuropsychological Tests; Outcome Assessment, Health Care; Piperidines; Placebos; Psychiatric Status Rating Scales; Psychomotor Performance; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; Treatment Outcome; United States

Individuals who have Mild Cognitive Impairment (MCI) may be in a transitional stage between aging and Alzheimer's disease (AD). The high rate of conversion from MCI to AD makes early treatment an important clinical issue. Recent evidence suggests that cognitive training intervention may reduce the rate of progression to AD.. To evaluate the efficacy of a NeuroPsychological Training (TNP) in patients with MCI who are treated with cholinesterase inhibitors (ChEIs), compared with patients MCI treated only with ChEIs and patients not treated, in a longitudinal, one year follow-up study.. One year longitudinal and retrospective comparison study of neuropsychological performances in 59 subjects affected by Mild Cognitive Impairment (MCI) according to Petersen's criteria. Fifteen subjects were randomised to receive TNP plus cholinesterase inhibitors; 22 subjects cholinesterase inhibitors alone and 22 subjects no treatment. All the subjects referring memory complaints, corroborated by an informant, underwent a multidimensional assessment concerning neuropsychological, behavioural and functional characteristics, at baseline and after one year follow-up.. Subjects without treatment maintained their cognitive, functional and behavioural status after one year; patients treated only with ChEIs improved in depressive symptoms whereas subjects treated with TNP and ChEIs showed significant improvements in different cognitive areas, such as memory, abstract reasoning and in behavioural disturbances, particularly depressive symptoms.. A long-term TNP in ChEIs-treated MCI subjects induces additional cognitive and mood benefits.

Topics: Activities of Daily Living; Aged; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Computer-Assisted Instruction; Donepezil; Female; Galantamine; Humans; Indans; Intelligence; Longitudinal Studies; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Nootropic Agents; Orientation; Phenylcarbamates; Piperidines; Problem Solving; Retrospective Studies; Rivastigmine; Software; Treatment Outcome

To determine whether an acetylcholinesterase inhibitor, such as donepezil, would improve memory or other cognitive/psychological functions in epilepsy patients with subjective memory complaints.. Twenty-three epilepsy patients with subjective memory difficulty were randomized to either 3 months of donepezil (10 mg/day) or 3 months of placebo treatment, and then crossed over to the other treatment arm. Patients and physicians were blinded to treatment phase throughout data acquisition. Assessment of memory and other cognitive functions, subjective memory, mood, and self-rated quality of life (QOL) and social functioning was performed at baseline and following completion of both treatment phases. Seizure frequency and severity as well as treatment emergent adverse effects were also monitored.. Donepezil treatment was not associated with improvement in memory or other cognitive functions, mood, social functioning or QOL. Comparable increases in self-rated memory functioning relative to baseline were evident during donepezil and placebo phases. Donepezil treatment was not associated with increased seizure frequency or severity. Similar to group results, analysis of change within individual patients as a function of treatment phase also showed neither significant benefit nor detriment associated with donepezil.. This study found no benefit on memory or other cognitive/psychological functions in a heterogeneous group of epilepsy patients with subjective memory difficulty. Further investigation would be required to determine whether individual patients, or those with particular epilepsy syndromes, might benefit from donepezil or other acetylcholinesterase inhibitors, or if a higher dosage might be effective.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy; Health Status; Humans; Indans; Memory Disorders; Neuropsychological Tests; Piperidines; Placebos; Quality of Life; Severity of Illness Index; Social Adjustment; Treatment Outcome

Perimenopausal and menopausal women are more likely to complain of memory loss than are premenopausal women, although the association between menopause and cognitive loss remains controversial. Recently published studies on the risks of hormone therapy have left many women and their physicians seeking effective nonhormonal treatments for menopausal symptoms, including cognitive loss.. This study investigated the efficacy of the cholinesterase agent donepezil in the treatment of menopause-related cognitive loss.. Community-dwelling women in natural menopause were recruited for a randomized, double-blind, placebo-controlled study of donepezil. To qualify for enrollment, the Brief Cognitive Rating Scale was used to determine cognitive symptoms, and women with depression were excluded. Subjects were randomized to receive either donepezil, commencing at 5 mg/d, or placebo. At week 6 of randomization, the dosage of donepezil was increased to 10 mg/d. Treatment continued throughout the 26-week study. The primary outcome measure was the overall change in neurocognitive test results over time. Outcome variables of test scores were analyzed before and after receipt of donepezil or placebo.. A total of 28 women aged 46 to 60 years were enrolled. Fourteen women were randomized to receive active drug, 14 to placebo. Two women dropped out of the placebo group. There were no statistically significant differences between treatment groups in post-/pre-dose mean score ratios. No interactions were statistically significant. The P values for tests of equal variances did not reveal a difference in the means. Subjective measures did show some trends toward improvement in memory and cognition.. Donepezil was no more effective than placebo in treating the symptoms of menopause- related memory and cognitive loss.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Memory Disorders; Menopause; Middle Aged; Piperidines; Treatment Outcome

Cholinesterase inhibitor (ChEI) medications (ie, donepezil, rivastigmine, and galantamine) have been useful in slowing the progression of the mild to moderate stages of Alzheimer's disease (AD). Findings supporting this have largely relied on a global error score from the Alzheimer's Disease Assessment Scale and have not described the nature of the memory problems. We examined this issue by comparing learning, recall, and recognition scores among 2 groups of mild to moderately demented AD patients. Participants were patients from a memory clinic who either were on ChEI treatment (AD+ChEI, n = 14) or had never taken a ChEI (AD-ChEI, n = 14). Participants underwent a comprehensive neuropsychological evaluation, including administration of the CERAD Word List Memory test. Results indicated no significant group difference for learning and delayed free recall, but the AD+ChEI group had significantly fewer errors than the AD-ChEI group on the CERAD Recognition test. Our findings provide preliminary evidence that the aspect of memory that is most affected by ChEIs appears to be facilitation of retention of new information in memory. The implications of this on clinical care and functional abilities as well as future directions are discussed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Mental Recall; Mental Status Schedule; Neuropsychological Tests; Phenylcarbamates; Piperidines; Retention, Psychology; Rivastigmine; Verbal Learning

To analyse the prospect of memory training for patients with organic brain damage.. Sixty-two patients with memory disorder were assigned to three different groups: a control group (n=16) with low dose memory training, a process oriented memory training group (POT) (n=24) and a group (ST) who was taught to compensate for memory problems with different strategies (n=22). Most of the patients had suffered a stroke. Inclusion criteria were medium to weak memory impairment defined by the patients' performance in the California Verbal Learning Test. Patients with complete amnesia were excluded. Specific care was taken that the groups did not differ in age, time since illness, duration of rehabilitation effort, verbal and performance IQ, memory and attention performance. The two treatment groups received 20 hours memory training, the low dose memory training control group 7 sessions.. The treatment groups improved in verbal and prospective memory, but only the group with POT experienced a significant improvement compared with the control group. Training effects were specific, i. e. they affected verbal memory, but were not encapsulated, i. e. generalized to the recall of prose passages and of appointments. The POT group also showed a statistically weak outperformance compared with the ST group and some attentional improvement as well.. Memory training is effective in patients with organic brain lesion, but only if applied frequently. Comparing the two training high intensity treatments, a POT focus seems to be superior to teaching a set of compensation strategies.

Topics: Aged; Analysis of Variance; Attention; Donepezil; Female; Humans; Indans; Intelligence Tests; Male; Memory Disorders; Mental Recall; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychomotor Performance; Psychotherapy, Group; Stroke; Stroke Rehabilitation; Verbal Learning

The present study used short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and short latency afferent inhibition (SAI) to evaluate motor cortex excitability in 16 diffuse axonal injury (DAI) patients with memory impairment and compared the data with those of 16 healthy controls. SAI was reduced in patients compared with controls (92+/-12 versus 39+/-11% of the test size; p<0.0001, unpaired t-test). DAI patients tended to have a high resting motor threshold (RMT) and less pronounced SICI and ICF than controls, but these differences were not significant. A single oral dose (3mg) of donepezil, an acetylcholinesterase inhibitor that is commonly used to treat Alzheimer's disease (AD), improved SAI in DAI patients with wide individual variations that ranged from an increase of 77-18% of test size. These findings suggest that measuring SAI may provide a means of probing the integrity of cholinergic networks in an injured human brain.

Topics: Adult; Afferent Pathways; Differential Threshold; Diffuse Axonal Injury; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Motor Cortex; Neural Inhibition; Nootropic Agents; Piperidines; Reaction Time; Transcranial Magnetic Stimulation

Substantial progress has been made in identifying how the treatment parameters used in electroconvulsive therapy (ECT) impact its cognitive side effects. However, there is limited information regarding the role of memory enhancers in post-ECT cognitive disturbances. We evaluated the therapeutic and prophylactic efficacy of the memory-enhancing drug donepezil hydrochloride on cognition of patients undergoing ECT.. A triple blind (the study subjects, clinician assessing the cognition, and the data analyst were unaware of subject allocation for trial assessment) randomized controlled trial was carried out in a General Hospital Psychiatry Unit. Subjects were randomized into 2 groups. One group received ECT with placebo, whereas the other group received ECT and donepezil (a memory-enhancing drug). Study participants were assessed in post-ECT period to analyze cognitive deficits and to compare the differences in 2 groups, as regards recovery of various aspects of cognition.. The post-ECT recovery of various components of cognition was more rapid in patients using donepezil as compared to those not given donepezil (P < 0.05).. This significant improvement in recovery time among patients receiving donepezil bears therapeutic implication in immediate post-ECT cognitive deficits.

Topics: Adult; Cognition; Donepezil; Electroconvulsive Therapy; Humans; Indans; Male; Memory; Memory Disorders; Nootropic Agents; Piperidines; Recovery of Function; Treatment Outcome

To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD).. Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects.. Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases.. Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Nootropic Agents; Parkinson Disease; Pilot Projects; Piperidines; Treatment Outcome

Acetylcholinesterase inhibitor treatment enhances cholinergic neurotransmission and may thus partially reverse EEG slowing and memory impairment in Alzheimer patients within short time.. We studied the short-term effects of treatment with either rivastigmine or donepezil on EEG and memory performance in a group of 35 Alzheimer patients in an open, controlled design.. Under a 1- or 2-week acetylcholinesterase inhibitor treatment, a decrease of global theta power and an improvement in the ADAS memory score were observed. However, compared to the control condition, only the theta power decrease remained significant and can be definitely considered a medication effect.. EEG spectral analysis could be shown to rapidly reflect the cerebral cholinergic action of short-term acetylcholinesterase inhibitor treatment. Whether this action is related to the therapeutic efficacy of this type of drug must be determined in further longitudinal studies.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Female; Humans; Indans; Male; Memory; Memory Disorders; Middle Aged; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Theta Rhythm; Time Factors; Treatment Outcome

To determine preliminarily whether donepezil will improve memory, behavior, and global function after chronic traumatic brain injury (TBI).. Sixteen-week open-label study.. Outpatient TBI rehabilitation program.. Four patients with chronic, severe TBI.. Donepezil 5mg daily for 8 weeks followed by 10mg daily for 4 weeks.. Memory measures included the Rey Auditory Verbal Learning Test (RAVLT), the Complex Figure Test (CFT), items from the Rivermead Behavioural Memory Test (RBMT), and a semantic fluency task. The Neuropsychiatric Inventory (NPI) evaluated behavior and affect. Function was assessed by using the FIM instrument and a clinical global impression of change.. On the RAVLT, the mean scores for learning and short- and long-term recall improved by 0.4, 1.04, and.83 standard deviations (SDs) above baseline, respectively. On the CFT, the mean scores for short-term recall and long-term recall improved by 1.56 and 1.38 SDs above baseline, respectively. A positive trend was observed on the RBMT and on the NPI subscales.. Donepezil may improve some aspects of memory and behavior in persons with chronic TBI. Randomized clinical trials are required to support these preliminary findings.

Topics: Adult; Brain Injuries; Chronic Disease; Donepezil; Humans; Indans; Male; Memory Disorders; Mental Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

Donepezil is an acetylcholinesterase inhibitor marketed for treatment of memory loss and behavioral deterioration associated with the acetylcholine deficit of Alzheimer's disease. We investigated the utility and tolerability of donepezil in nongeriatric affective illness for treatment of psychotropic-induced memory loss, dry mouth, and constipation.. Nondemented outpatients with stabilized DSM-IV affective illness took 5 mg/day of donepezil for 3 weeks and then increased to 10 mg/day in open trials. Self-rating scales of target symptoms were completed by patients before and 3 to 4 weeks after starting each dose condition. Patients who chose to continue donepezil therapy returned for clinical monitoring every 4 to 8 weeks.. Eleven women and 11 men (mean +/- SD age = 45.4+/-8.5 years) completed donepezil trials. Nineteen patients with memory loss rated improvement while taking 5 mg/day of donepezil (p<.001); subsequently, 6 rated further improvement with 10 mg/day (p = .057). Donepezil, 5 mg/day, also reduced ratings of dry mouth (N = 16; p<.001) and constipation (N = 11; p<.05). Side effects included insomnia, nausea, vomiting, and diarrhea; surprisingly, 2 bipolar patients became manic within hours of starting donepezil. Sixteen patients (72%) continued donepezil for an average of 7 months. Consideration of family histories suggested that donepezil response in affective illness may be an early indicator of vulnerability to dementia of the Alzheimer's type.. (1) Donepezil can reduce memory loss, dry mouth, and constipation in nongeriatric affective patients, but may trigger mania; and (2) long-term follow-up will reveal the predictive value for dementia of donepezil's memory restoration in nongeriatric subjects.

Topics: Adult; Ambulatory Care; Cholinesterase Inhibitors; Constipation; Depressive Disorder; Diarrhea; Dizziness; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Piperidines; Psychotropic Drugs; Sleep Initiation and Maintenance Disorders; Xerostomia

Sabeluzole, a new benzothiazol derivative, has shown positive effects on memory function in animals and in normal volunteers. The present study reports the results of sabeluzole, in memory-impaired patients with localization-related (partial) epilepsy. A randomized, double-blind placebo-controlled parallel-group design was used. A total of 38 patients entered a prospective baseline. Five patients dropped out from the study, thus 33 patients were randomly assigned to either a 12-weeks treatment with sabeluzole (n = 14) or placebo (n = 19). The treatment phase was preceded by a titration phase of 4 weeks to obtain serum levels of sabeluzole between 50 and 130 ng/ml. In order to maintain blindness, a sham titration was carried out in the placebo group. The number of 'responders', i.e. patients with a > 1 SD improvement on at least three of the memory tests was 9 out of 14 (64.3%) in the sabeluzole group and 7 out of 19 (36.8%) in the placebo group. This suggests a clinically relevant effect of sabeluzole. The analysis of the memory tests showed a statistically significant improvement with sabeluzole on the verbal long-term memory test. This could represent a specific drug effect and is in line with previous results of normal volunteer studies that also found improvement mainly restricted to the area of verbal long-term memory.

Topics: Adult; Affect; Cognition; Double-Blind Method; Epilepsy; Female; Functional Laterality; Humans; Intelligence Tests; Male; Memory; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Piperidines; Psychomotor Performance; Reaction Time; Speech; Thiazoles

Alzheimer's disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. ​Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Disease Models, Animal; Humans; Male; Maze Learning; Memory Disorders; Neurodegenerative Diseases; Piperidines; Rats; Rats, Wistar; Streptozocin

Increasing evidence shows the interaction effect of cannabinoids and sleep on cognitive functions. In the present study, we aimed to investigate the interaction effect of cannabinoids type 1 receptor (CB1r) in the CA1 hippocampal region and sleep deprivation (SD) on passive avoidance memory and depressive-like behavior in male Wistar rats. We used water box apparatus to induce total SD (TSD) for 24 h. The shuttle-box was applied to assess passive avoidance memory and locomotion apparatus was applied to assess locomotor activity. Forced swim test (FST) was used to evaluate rat's behavior. ACPA (CB1r agonist) at the doses of 0.01, 0.001 and 0.0001 μg/rat, and AM251 (CB1r antagonist) at the doses of 100, 10 and 1 ng/rat were injected intra-CA1, five minutes after training via stereotaxic surgery. Results showed SD impaired memory. ACPA at the doses of 0.01 and 0.001 μg/rat impaired memory and at all doses did not alter the effect of SD on memory. AM251 by itself did not alter memory, while at lowest dose (1 ng/rat) restored SD-induced memory deficit. Both drugs induced depressive-like behavior in a dose-dependent manner. Furthermore, both drugs decreased swimming at some doses (ACPA at 0.0001 μg/rat, AM251 at 0.001 and 0.01 ng/rat). Also, ACPA at the highest dose increased climbing of SD rats. In conclusion, we suggest CB1r may interact with the effect of SD on memory. Additionally, cannabinoids may show a dose-dependent manner in modulating mood and behavior. Interestingly, CB1r agonists and antagonists may exhibit a similar effect in some behavioral assessments.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Behavior, Animal; CA1 Region, Hippocampal; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Locomotion; Male; Memory Disorders; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sleep Deprivation; Swimming

Dysfunction of cholinergic system plays an important role in disease associated with cognitive blockage, such as Alzheimer's disease (AD). Central administration of scopolamine, an antagonist of acetylcholine receptor, could induce memory impairment in mice. Endocannabinoid system was also implicated in AD, as two peptides agonists of cannabinoid 1 receptor (CB1R), (m)RVD-hemopressin (α) (RVD) and (m)VD-hemopressin (α) (VD) have been reported to inhibit the AD-relating impairment in animal and cell models. More than one-third of the cholinergic cells expressed CB1R, so we speculated that RVD and VD might have ability to inhibit the memory-impairing effect of scopolamine. Our results showed RVD and VD ameliorated the memory toxicity of scopolamine, and the effects of the two peptides could be blocked by CB1R antagonists hemopressin (Hp) and AM251 in novel object and object location recognition tasks in mice. This study suggested that RVD and VD might be potential compounds for the treatment of the disease associated with impairment of cholinergic system.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Endocannabinoids; Hemoglobins; Humans; Memory Disorders; Mice; Oligopeptides; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Scopolamine

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aβ)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aβ-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aβ-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3β-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Eicosanoids; Epoxide Hydrolases; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Memory Disorders; Mice; Mice, Inbred C57BL; Phenylurea Compounds; Piperidines; Signal Transduction; Spatial Learning

Sleep is a circadian rhythm that is modulated by endogenous circadian clock located in the suprachiasmatic nucleus (SCN). Sleep modulates memory acquisition and promotes memory consolidation. Studies have shown that sleep deprivation (SD) impairs different types of memory including passive avoidance. Furthermore, the hippocampus plays a significant role in modulating passive avoidance memory. On the other hand, 5-HT4 receptors are expressed in the hippocampus and involved in learning and memory processes. In this study, we aimed to investigate the role of CA1 hippocampal 5-HT4 receptors in memory acquisition impairment induced by total sleep deprivation (TSD: 24 h) and REM sleep deprivation (RSD: 24 h). The water box apparatus was used to induce TSD, while multi-platform apparatus was applied to induce RSD. Passive avoidance memory test was also used to evaluate memory acquisition. The results showed that, intra-CA1 pre-training injection of RS67333 (5-HT4 agonist) and RS23597 (5-HT4 antagonist) at the doses of 0.01 and 0.1 µg/rat decreased memory acquisition, but did not alter pain perception and locomotor activity. Furthermore, TSD and RSD decreased memory acquisition; however, only TSD decreased locomotor activity and induced analgesic effect. The sub-threshold doses of RS67333 and RS23597, 0.001 and 0.0001 µg/rat, respectively, reversed the effect of TSD on memory acquisition and locomotor activity. In addition, only RS23597 reversed TSD-induced analgesia. In RSD condition, the subthreshold dose of RS23597 improved RSD-induced memory acquisition deficit. In conclusion, CA1 hippocampal 5-HT4 receptors play an important role in TSD/RSD-induced cognitive alterations.

Topics: Aniline Compounds; Animals; Avoidance Learning; CA1 Region, Hippocampal; Male; Memory Consolidation; Memory Disorders; Microinjections; Motor Activity; Pain Perception; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Sleep Deprivation

We still do not have effective treatment for hippocampal demyelination and memory deficit, the two common comorbidities in multiple sclerosis (MS). This study aimed to assess the therapeutic effect of Piperine (the main alkaloid of black pepper) in an experimental model of demyelination.. Demyelination was induced in male Wistar rats by bilateral injection of lysolecithin (LPC) into the CA1 region of the hippocampus. Piperine (5, 10, 20 mg/kg) was daily injected intraperitoneally three days post LPC injection for ten days. The spatial memory was examined by the Morris water maze task. Demyelination and astrocyte activation were assessed by an immunohistological study. The gene expression analysis of TNF-α, IL1-β, NF-κB, IL-10, Foxp3, iNOS, Nrf2, HO1, MBP, and BDNF was done using qPCR. The total antioxidant capacity of hippocampal tissue was measured using FRAP assay.. Our results showed that piperine improved the memory performance and myelin repair in the hippocampal demyelination model. Piperine inhibited iNOS expression concomitant with enhanced expression levels of Nrf2, HO1 and the total antioxidant capacity in the hippocampal tissue. Piperine treatment significantly reduced the gene expression level of TNF-α, IL1-β, NF-κB, and glial activation in the injured area; however, the mRNA level of IL-10, Foxp3, BDNF and MBP were significantly increased.. We found piperine to be an effective treatment for spatial memory impairment and myelin repair in the hippocampal demyelination model. However, further experimental evidence is needed to investigate the precise mechanisms underlying piperine as a promising therapeutic target in MS patients.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cytokines; Demyelinating Diseases; Gene Expression Regulation; Hippocampus; Lysophosphatidylcholines; Male; Maze Learning; Memory Disorders; Models, Animal; Myelin Sheath; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spatial Memory

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD). Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet. In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Neurotoxicity Syndromes; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Streptozocin; Time Factors

N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-L-valine methyl ester (5F-AMB) is a synthetic cannabinoid that has been distributed recently. Although inhalation of 5F-AMB produces adverse effects, such as impaired memory and disturbed consciousness, in humans, the psychopharmacological effects of 5F-AMB in rodents have not been investigated.. We first examined the effects of intraperitoneal and intracerebroventricular injections of 5F-AMB on anxiety-like behavior and locomotor activity in the open field (OF) test and recognition memory in the novel object recognition test (NOR) in C57BL/6J mice. We also examined whether a cannabinoid 1 (CB1) receptor antagonist AM251 blocks the effects of 5F-AMB. We next examined the effects of 5F-AMB infusion into the medial prefrontal cortex (mPFC), a brain region associated with anxiety and memory, on these tests.. Intraperitoneal injection of 5F-AMB (0.3 mg/kg) dramatically decreased locomotor activity in the OF, and this effect was partially reversed by AM251 (3 mg/kg). Intracerebroventricular infusion of 5F-AMB (10 nmol) produced an anxiolytic effect in the OF and impaired acquisition, but not retrieval, of recognition memory in the NOR, and these effects were blocked by co-infusion of AM251 (1.8 nmol). Bilateral intra-mPFC infusion of 5F-AMB (10 pmol/side) similarly produced impaired recognition memory acquisition, but no anxiolytic effect.. The results demonstrate that centrally administered 5F-AMB produces anxiolytic effect and impaired recognition memory acquisition via activation of CB1 receptors, while systemic 5F-AMB severely impaired locomotor activity. The mPFC is involved in 5F-AMB-induced impairment of recognition memory acquisition. However, other brain region(s) may contribute to the 5F-AMB-induced anxiolytic effect.

Topics: Animals; Anxiety; Cannabinoids; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Piperidines; Prefrontal Cortex; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrogen; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Streptozocin

Topics: Activating Transcription Factor 6; Animals; Carbamates; Cognition Disorders; Disease Models, Animal; Hippocampus; Humans; Huntington Disease; Kv Channel-Interacting Proteins; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neuronal Calcium-Sensor Proteins; Neurons; Piperidines; Rotarod Performance Test

The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats.. STZ (3mg/kg bilaterally) as intracerebroventrical (icv) route was administered on day 1 and 3 in rats. Donepezil (5mg/kg/day po), used as standard, and BA (5, 10 and 15mg/kg/day po) were administered after 1h of 1st STZ infusion up to 21days. Object recognition task (ORT) for non-spatial, Morris water maze (MWM) for spatial and locomotor activity were performed to evaluate behavioral changes in rats. On 22nd day, animals were decapitated and hippocampus was separated to perform biochemical (AChE, LPO, GSH, nitrite), neuroinflammatory (TNF-α, IL-1β, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis.. STZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokine's level and altered NTs level. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA dose dependently (5, 10 and 15mg/kg) significantly restore STZ induced memory changes and pathological abnormalities in rat brain.. The findings of the current study suggests that BA protect rat brain from STZ induced neuronal damage via acting through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders especially AD.

Topics: Acetylcholinesterase; Animals; Betulinic Acid; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Glutathione; Hippocampus; Indans; Inflammation; Injections, Intraventricular; Male; Maze Learning; Memory; Memory Disorders; Neuroprotective Agents; Neurotransmitter Agents; Oxidative Stress; Pentacyclic Triterpenes; Piperidines; Rats; Rats, Wistar; Streptozocin; Triterpenes

Pharmacological inhibition of soluble epoxide hydrolase (sEH) enhances the synaptic function in the CNS and has a protective role in cognitive decline. We hypothesized that the sEH inhibitor TPPU might prevent the diabetes-induced decline in learning and memory which is associated with an alteration in the level of neurotransmitters and oxidative stress.. Type 1 diabetes was induced in rats and the animals were treated with TPPU for 8 weeks. The learning and memory functions were assessed by the Barnes maze and a step-down test. Indicators of oxidative stress, levels of neurotransmitters, and activity of acetylcholinesterase were measured in the discrete regions of the brain.. Our results revealed that treatment with TPPU significantly improves learning and memory performance in diabetic rats along with decreasing the level of blood sugar. Moreover, treatment with TPPU significantly prevented the diabetes-induced alteration in levels of neurotransmitters, the activity of acetylcholinesterase and preserved anti-oxidant defence system.. Inhibition of the sEH alleviates diabetes-induced decline in learning and memory.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 1; Enzyme Inhibitors; Epoxide Hydrolases; Learning; Male; Memory Disorders; Phenylurea Compounds; Piperidines; Rats; Rats, Wistar

Vesicular acetylcholine transporter (VAChT) is a rate-limiting factor for synaptic acetylcholine transport. Our study focused on whether [. Morris water maze test was used to evaluate learning and memory deficits in pilocarpine-induced chronic epilepsy rats 12 weeks after status epilepticus. Interictal [. Epileptic rats exhibited significant memory deficits in Morris water maze test. [. [

Topics: Acholeplasmataceae; Animals; Brain; Chronic Disease; Disease Models, Animal; Epilepsy; Fluorodeoxyglucose F18; Male; Maze Learning; Memory Disorders; Muscarinic Agonists; Naphthols; Pilocarpine; Piperidines; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Vesicular Acetylcholine Transport Proteins

Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies.. We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis.. To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms.. Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay.. These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.

Topics: Acetamides; Animals; Association Learning; Benzamides; Calcium Channel Blockers; Calcium Channels, T-Type; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Locomotion; Male; Memory Disorders; Piperidines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome. Paracetamol (APAP) causes, in high doses, a hepatic injury. Alogliptin (ALO), with its 100% oral bioavailability, may be able to reverse the acute hepatic injury and memory impairments.. Forty rats were divided into four groups as follows; Normal Control Group, APAP intoxicated group, ALO and SIL groups. Behavioral tests (Morris water maze, Y-maze spontaneous alteration, and novel object recognition test) were performed together with evaluating HE score. Neurotransmitters (gamma-aminobutyric acid, glutamate, dopamine, serotonin, norepinephrine and acetylcholine), as well as acetylcholinesterase activity, were determined in the hippocampus. Also, hepatotoxicity markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and ammonia) were measured in blood. Additionally, transforming growth factor beta 1, tumor necrosis factor alpha, cytochrome c, granzyme B and caspase-3, coiled-coil Moesin-like BCL-interacting protein 1 "beclin-1", cellular FLICE-like inhibitory protein, protein 53, TNF-α related apoptosis-inducing ligand, Fas-ligand and alpha-smooth muscle actin were measured in liver homogenate. Moreover, the histopathological investigation was performed.. APAP was able to disturb neurotransmitters which were mirrored in the performance of rats in the behavioral test. Most hepatotoxicity, apoptosis and inflammation indicators were elevated after APAP administration, while beclin-1 (autophagy marker) was declined. The tested drugs, both, reversed most of the last mentioned parameters but ALO was more efficient in reducing TGF-β1, α-SMA, TNF-α and ALP as well as increasing % alteration.. ALO and SIL elicited anti-apoptotic, anti-inflammatory and autophagic effects on paracetamol-damaged liver cells and improved memory impairments of HE.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Behavior, Animal; Biomarkers; Chemical and Drug Induced Liver Injury; Dipeptidyl-Peptidase IV Inhibitors; Hepatic Encephalopathy; Hydroxyethylrutoside; Male; Maze Learning; Memory; Memory Disorders; Piperidines; Rats; Rats, Wistar; Uracil

Alzheimer's disease (AD) is believed to develop due to deposition of β-amyloid (Aβ) peptide. Hence, efforts are being made to develop potent drug that target amyloid hypothesis.. The present study explores the effect of the seaweed Gelidiella acerosa (Forsskål) Feldmann & Hamel (Gelidiellaceae) against Aβ 25-35 peptide in Swiss albino mice.. The animals were administered through intracerebroventricular (ICV) injection with the Aβ 25-35 peptide (10 μg/10 μL/ICV site) on 21st day of the pretreatment of G. acerosa (whole plant) benzene extract (200 and 400 mg/kg bw). On day 30, animals were sacrificed and brain tissue homogenate was prepared. The activities of AChE, BuChE, b-secretase, MAO-B, and caspase-3 were determined, and Bax expression was assessed by Western blotting.. Gelidiella acerosa benzene extract restored the level of antioxidant enzymes and prevented lipid and protein oxidation significantly (p < 0.05). The extract protected the mice from cholinergic deficit significantly (p < 0.05) by inhibiting the activities of AChE and BuChE, which was about 0.116 ± 0.0088 U/mg of protein and 0.011 ± 0.0014 U/mg of protein respectively, which was otherwise increased in peptide-treated group (0.155 ± 0.007 U/mg of protein and 0.015 ± 0.0012 U/mg of protein respectively). Interestingly, G. acerosa benzene extract inhibited β-secretase and MAO-B activity. Reduction (p < 0.05) in level of caspase-3 activity and Bax expression suggests that G. acerosa protects the cells from apoptosis.. The results suggest that G. acerosa possesses excellent neuroprotective potential against peptide mediated toxicity under in vivo conditions.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Apoptosis; bcl-2-Associated X Protein; Behavior, Animal; Brain; Butyrylcholinesterase; Caspase 3; Disease Models, Animal; Donepezil; Escape Reaction; GPI-Linked Proteins; Indans; Lipid Peroxidation; Male; Maze Learning; Memory; Memory Disorders; Mice; Monoamine Oxidase; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Peptide Fragments; Piperidines; Protein Carbonylation; Seaweed

Dysfunction in topographical memory is a core feature of several neurological disorders. There is a large unmet medical need to address learning and memory deficits as a whole in central nervous system disease. There are considerable efforts to identify pro-cognitive compounds but current methods are either lengthy or labour intensive. Our test used a two chamber apparatus and is based on the preference of rodents to explore novel environments. It was used firstly to assess topographical memory in mice at different retention intervals (RI) and secondly to investigate the effect of three drugs reported to be beneficial for cognitive decline associated with Alzheimer's disease, namely: donepezil, memantine and levetiracetam. Animals show good memory performance at all RIs tested under four hours. At the four-hour RI, animals show a significantly poorer memory performance which can be rescued using donepezil, memantine and levetiracetam. Using this test we established and validated a spatial recognition paradigm to address topographical memory in mice by showing a decremental time-induced forgetting response and reversing this decrease in performance using pharmacological tools. The spatial recognition test differs from more commonly used visuospatial laboratory tests in both throughput capability and potentially neuroanatomical substrate. This test has the potential to be used to assess cognitive performance in transgenic animals, disease models and to screen putative cognitive enhancers or depressors.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Donepezil; Indans; Levetiracetam; Male; Maze Learning; Memantine; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Piperidines; Piracetam; Recognition, Psychology

Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations are found in 90% of patients with neurofibromatosis, a syndrome associated with disabling cognitive impairment. Drosophila studies have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 in cognitive performance. In addition, pharmacologic inhibition of Alk improves cognitive performance in heterozygous NF1 mutant flies. In this study, we tested whether pharmacological inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments. Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor. These data support the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Cognitive Dysfunction; Disease Models, Animal; Female; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Knockout; Neurofibromatosis 1; Nootropic Agents; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Spatial Memory; Swimming

It is widely assumed that the upcoming therapeutics for Alzheimer's disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task.. For spontaneous alternation behavior, combination of 1 mg/kg galantamine and 0.5 mg/kg RS-67333 fully reversed the deficit. In the passive avoidance task, no sub-efficacious doses could be found in the retention paradigm, but a beneficial effect of the association has been demonstrated in the acquisition paradigm.. Mnesic effects of galantamine can be thus potentiated by activation of 5-HT4R. Such a combination treatment might (1) strengthen symptomatic relief, (2) attenuate adverse effects given the lower doses of each compound required, and (3) afford a disease-modifying effect given the known action of 5-HT4R on amyloidogenesis cascade.

Topics: Allosteric Regulation; Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Galantamine; Male; Memory Disorders; Mice; Nicotinic Antagonists; Piperidines; Receptors, Nicotinic; Receptors, Serotonin, 5-HT4; Scopolamine; Serotonin 5-HT4 Receptor Agonists

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

Topics: Aging; Alzheimer Disease; Animals; Cheirogaleidae; Disease Models, Animal; Donepezil; Indans; Male; Memantine; Memory Disorders; Piperidines; Sleep Deprivation; Spatial Memory

Ethanol consumption induces neurological disorders including cognitive dysfunction. Oxidative damage is considered a likely cause of cognitive deficits. We aimed to investigate the effects of rosmarinic acid (RA) in different doses for 30 days on chronic ethanol-induced cognitive dysfunction using the passive avoidance learning (PAL) and memory task in comparison with donepezil, a reference drug. We also evaluated the levels of superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation in hippocampus as possible mechanisms.. Memory impairment was induced by 15% w/v ethanol (2 g/kg, i.g.) administration for 30 days. RA (8, 16, and 32 mg/kg, i.g.) or donepezil (2 mg/kg, i.g.) was administered 30 minutes before ethanol. The acquisition trial was done 1 hour after the last administration of RA and donepezil. At the end, animals were weighed and hippocami were isolated for analyzing of oxidant/antioxidant markers.. Ethanol caused cognition deficits in the PAL and memory task. While RA 16 and 32 mg/kg improved cognition in control rats, it prevented learning and memory deficits of alcoholic groups. RA 8 mg/kg did not influence cognitive function in both control and alcoholic rats. RA 32 mg/kg had comparable effects with donepezil in prevention of acquisition and retention memory impairment. The higher doses of RA not only prevented increased lipid peroxidation and nitrite content but also decreased SOD, CAT, GSH, and FRAP levels in alcoholic groups and exerted antioxidant effects in non-alcoholic rats.. We showed that RA administration dose-dependently prevented cognitive impairment induced by chronic ethanol in PAL and memory and disturbed oxidant/antioxidant status as a possible mechanism. The antioxidant, anticholinesterase, and neuroprotective properties of RA may be involved in the observed effects. Therefore, RA represents a potential therapeutic option against chronic ethanol-induced amnesia which deserves consideration and further examination.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Antioxidants; Avoidance Learning; Behavior, Animal; Biomarkers; Cholinesterase Inhibitors; Cinnamates; Depsides; Dietary Supplements; Donepezil; Exploratory Behavior; Hippocampus; Indans; Learning Disabilities; Lipid Peroxidation; Male; Memory Disorders; Neurons; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Piperidines; Random Allocation; Rats, Wistar; Rosmarinic Acid

Recently, combination therapy involving cholinesterase (ChE) inhibitor with other neuroprotective agents has shown better desirable effect in the management/prevention of dementia but limited information is available on their effect with dietary polyphenols. Hence, this study sought to assess the combined pretreatment effect of curcumin, the major polyphenolic compound of turmeric (Curcuma longa) rhizomes, with donepezil, a cholinesterase inhibitor, on cognitive function in scopolamine-induced memory impairment in rats. Rats were pretreated with curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) via oral administration (p.o.) for seven successive days. Dementia was induced at the end of the treatment period by a single injection of scopolamine (1 mg/kg) via intraperitoneal (i.p.) administration. Thereafter, the changes in spatial and episodic memory were conducted; then, the estimation of some biochemical parameters associated with cognitive function was determined. Scopolamine-treated rats showed impaired learning and memory and increased activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), adenosine deaminase (ADA), and lipid peroxidation with a concomitant decreased in levels of nitric oxide (NO) and reduced glutathione (GSH), superoxide dismutase (SOD), and catalase activities when compared with control. However, combination of curcumin and donepezil improves learning and memory activity associated with inhibitory effect on AChE, BuChE, and ADA activities as compared to control. In addition, combined pretreatment significantly decreased lipid peroxidation and increased levels of NO and antioxidant status when compared with scopolamine-treated rats. This finding supports the concept that the combination strategy might be an alternative therapy in the management/prevention of neurological disorders. Thus, the observed anti-amnestic effect could be linked to their inhibitory effect on key enzyme of cholinergic system associated with memory function.

Topics: Adenosine Deaminase; Animals; Brain; Catalase; Cholinergic Neurons; Cholinesterase Inhibitors; Curcumin; Donepezil; Drug Synergism; Glutathione; Indans; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Nitric Oxide; Piperidines; Rats; Recognition, Psychology; Scopolamine; Superoxide Dismutase

The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia.

Topics: Acetylcholinesterase; Aging; Alzheimer Disease; Animals; Antioxidants; Brain; Cholinesterase Inhibitors; Donepezil; Female; Indans; Inflammation; Learning; Male; Maze Learning; Memory Disorders; Mice; Neutrophil Infiltration; Oxidative Stress; Phosphodiesterase 4 Inhibitors; Piperidines; Plaque, Amyloid; Rolipram; Streptozocin

The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Cell Line, Tumor; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Humans; Indans; Interleukin-1beta; Male; Memory Disorders; Nootropic Agents; Peptide Fragments; Piperidines; Protein Aggregation, Pathological; Random Allocation; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Gumiganghwal-tang (GT) is a traditional herbal medicine that is widely used for its anti-inflammatory, analgesic, and antipyretic actions. Fermented GT has been reported to inhibit acetylcholinesterase (AChE) activity and to exert a neuroprotective effect. In this study, we investigated the effect of fermented GT against scopolamine-induced memory impairment in mice using the Morris water maze and passive avoidance tests. The results of the Morris water maze test indicated that fermented GT significantly decreased escape latency, as compared with that observed in the scopolamine-treated group. In the prove test, fermented GT attenuated the decreased time spent in the target quadrant observed after scopolamine treatment. The results of the passive avoidance test indicated that the treatment with fermented GT increased latency time when compared with the scopolamine-treated group. Moreover, fermented GT inhibited AChE activity in the hippocampi of the treated mice. These results suggest that fermented GT reduced scopolamine-induced amnesia in mice through AChE inhibition. Therefore, we hypothesize that fermented GT may be a useful therapeutic agent for the prevention or treatment of neurodegenerative diseases.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Behavior, Animal; Cholinergic Antagonists; Cholinesterase Inhibitors; Dietary Supplements; Disease Models, Animal; Donepezil; Fermentation; GPI-Linked Proteins; Hippocampus; Indans; Male; Maze Learning; Memory Disorders; Mice, Inbred ICR; Muscarinic Antagonists; Nerve Tissue Proteins; Neurons; Nootropic Agents; Piperidines; Plant Extracts; Republic of Korea; Scopolamine

The present study investigates the effects of 5-HT4 receptors of the nucleus accumbens (NAc) shell on the impairment of emotional memory consolidation induced by cannabinoid CB1 receptor stimulation. The elevated plus maze test-retest paradigm was used to assess memory in adult male Wistar rats. Intra-NAc shell administration of ACPA (selective cannabinoid CB1 receptor agonist 0.006 µg/rat) and RS23597 (5-HT4 receptor antagonist 0.01 µg/rat), immediately after training, decreased emotional memory consolidation, suggesting a drug-induced amnesia, whereas post-training intra-NAc shell microinjections of RS67333 (5-HT4 receptor agonist 0.016 µg/rat) increased emotional memory consolidation. Interestingly, RS67333 exerted a dual effect on ACPA-induced behaviors, potentiating and restoring amnesia caused by the subthreshold and effective doses of ACPA, respectively. However, neither RS23597 nor AM251 (CB1 receptor antagonist 30, 60 and 120 ng/rat) affected emotional memory consolidation. Nonetheless, a subthreshold dose of AM251 (120 ng/rat) reversed the amnesia induced by ACPA (0.006 µg/rat) and RS23597 (0.01 µg/rat). None of the above doses altered the locomotor activity. In conclusion, our results suggest that the NAc-shell 5-HT4 receptors are involved in the modulation of ACPA-induced amnesia.

Topics: Aniline Compounds; Animals; Arachidonic Acids; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Emotions; Male; Maze Learning; Memory Consolidation; Memory Disorders; Motor Activity; Nootropic Agents; Nucleus Accumbens; Piperidines; Pyrazoles; Random Allocation; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Drugs activating the sigma-1 (σ1) chaperone protein are anti-amnesic and neuroprotective in neurodegenerative pathologies like Alzheimer's disease (AD). Since these so-called σ1 receptor (σ1R) agonists modulate cholinergic and glutamatergic systems in a variety of physiological responses, we addressed their putative additive/synergistic action in combination with cholinergic or glutamatergic drugs. The selective σ1 agonist PRE-084, or the non-selective σ1 drug ANAVEX2-73 was combined with the acetylcholinesterase inhibitor donepezil or the NMDA receptor antagonist memantine in the nontransgenic mouse model of AD-like memory impairments induced by intracerebroventricular injection of oligomeric Aβ25-35 peptide. Two behavioral tests, spontaneous alternation and passive avoidance response, were used in parallel and both protective and symptomatic effects were examined. After determination of the minimally active doses for each compound, the combinations were tested and the combination index (CI) calculated. Combinations between the σ1 agonists and donepezil showed a synergic protective effect, with CI<1, whereas the combinations with memantine showed an antagonist effect, with CI>1. Symptomatic effects appeared only additive for all combinations, with CI=1. A pharmacological analysis of the PRE-084+donepezil combination revealed that the synergy could be due to an inter-related mechanism involving α7 nicotinic ACh receptors and σ1R. These results demonstrated that σ1 drugs do not only offer a protective potential alone but also in combination with other therapeutic agents. The nature of neuromodulatory molecular chaperone of the σ1R could eventually lead to synergistic combinations.

Topics: Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Drug Synergism; Excitatory Amino Acid Antagonists; Furans; Indans; Male; Memantine; Memory Disorders; Mice; Morpholines; Neuroprotective Agents; Peptide Fragments; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sigma-1 Receptor

Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.

Topics: Animals; Avoidance Learning; Benzothiazoles; Cholinesterase Inhibitors; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Histamine H3 Antagonists; Indans; Male; Memory; Memory Disorders; Nootropic Agents; Phenoxypropanolamines; Piperidines; Pyrilamine; Pyrroles; Quinazolines; Random Allocation; Rats, Wistar; Receptors, Histamine H3

The possible interactions between the cannabinoid and serotonin systems in the regions of the brain involved in emotional learning and memory formation have been studied by some researchers. In view of the key role of the amygdala in the acquisition and expression of fear memory, we investigated the involvement of basolateral amygdala (BLA) serotonin 5-HT4 receptors in arachidonylcyclopropylamide (ACPA; selective CB1 cannabinoid receptor agonist)-induced fear memory consolidation impairment. In our study, a context and tone fear conditioning apparatus was used for testing fear conditioning in adult male NMRI mice. The results showed that intraperitoneal administration of ACPA 0.5 or 0.05, 0.1 and 0.5mg/kg immediately after training decreased the percentage of freezing time in context or tone fear conditioning respectively, suggesting a context- or tone-dependent fear memory consolidation impairment. Post-training intra-BLA microinjections of RS67333, as 5-HT4 serotonin receptor agonist, at doses of 0.025 and 0.05 µg/mouse also impaired context or tone memory consolidation, while RS23597, as 5-HT4 serotonin receptor antagonist, did not produce a marked difference in both fear memories as compared with the control group. Moreover, a subthreshold dose of RS67333 did not alter ACPA response in both fear conditionings. Interestingly, a subthreshold dose of RS23597 potentiated or reversed ACPA response at the dose of 0.01 or 0.05 respectively. It is concluded that BLA serotonin 5-HT4 receptors are involved in tone-dependent fear memory consolidation impairment induced by CB1 activation using ACPA, suggesting a modulatory role for serotonin 5-HT4 receptor.

Topics: Acoustic Stimulation; Amygdala; Analysis of Variance; Aniline Compounds; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Conditioning, Classical; Dose-Response Relationship, Drug; Fear; Male; Memory Disorders; Mice; Microinjections; Piperidines; Reaction Time; Serotonin; Serotonin Agents

The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antineoplastic Agents; Cognition Disorders; Cyclin-Dependent Kinases; Disease Models, Animal; Flavonoids; Frontal Lobe; Hippocampus; Male; Memory; Memory Disorders; Mice; Neurons; Peptide Fragments; Piperidines

The current study was designed to examine the involvement of cannabinoid CB1 receptors in the basolateral amygdala (BLA) in scopolamine-induced memory impairment in adult male Wistar rats. The animals were bilaterally implanted with the cannulas in the BLA and submitted to a step-through type passive avoidance task to measure the memory formation. The results showed that intraperitoneal (i.p.) administration of different doses of scopolamine (0.5-1.5mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 1-4ng/rat), into the BLA significantly improved scopolamine-induced memory consolidation impairment. On the other hand, co-administration of AM251, a cannabinoid CB1 receptor antagonist (0.25-1ng/rat, intra-BLA), with an ineffective dose of scopolamine (0.5mg/kg, i.p.), significantly impaired memory consolidation and mimicked the response of a higher dose of scopolamine. It is important to note that post-training intra-BLA microinjections of the same doses of ACPA or AM251 alone had no effect on memory consolidation. Moreover, the blockade of the BLA CB1 receptors by 0.3ng/rat of AM251 prevented ACPA-induced improvement of the scopolamine response. In view of the known actions of the drugs used, the present data pointed to the involvement of the BLA CB1 receptors in scopolamine-induced memory consolidation impairment. Furthermore, it seems that a functional interaction between the BLA endocannabinoid and cholinergic muscarinic systems may be critical for memory formation.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Basolateral Nuclear Complex; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Male; Memory Consolidation; Memory Disorders; Nootropic Agents; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Scopolamine

Childhood absence epilepsy (CAE) is often comorbid with behavioral and cognitive symptoms, including impaired visual memory. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is an animal model closely resembling CAE; however, cognition in GAERS is poorly understood. Crossmodal object recognition (CMOR) is a recently developed memory task that examines not only purely visual and tactile memory, but also requires rodents to integrate sensory information about objects gained from tactile exploration to enable visual recognition. Both the visual and crossmodal variations of the CMOR task rely on the perirhinal cortex, an area with dense expression of T-type calcium channels. GAERS express a gain-in-function missense mutation in the Cav3.2 T-type calcium channel gene. Therefore, we tested whether the T-type calcium channel blocker Z944 dose dependently (1, 3, 10mg/kg; i.p.) altered CMOR memory in GAERS compared to the non-epileptic control (NEC) strain. GAERS demonstrated recognition memory deficits in the visual and crossmodal variations of the CMOR task that were reversed by the highest dose of Z944. Electroencephalogram recordings determined that deficits in CMOR memory in GAERS were not the result of seizures during task performance. In contrast, NEC showed a decrease in CMOR memory following Z944 treatment. These findings suggest that T-type calcium channels mediate CMOR in both the GAERS and NEC strains. Future research into the therapeutic potential of T-type calcium channel regulation may be particularly fruitful for the treatment of CAE and other disorders characterized by visual memory deficits.

Topics: Acetamides; Animals; Benzamides; Calcium Channels, T-Type; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Female; Male; Memory; Memory Disorders; Piperidines; Touch

Ferulic acid (FA) acts as a powerful antioxidant against various age-related diseases. To investigate the effect and underlying mechanism of FA against d-galactose(d-gal)-induced memory deficit, mice were injected with d-gal to induce memory impairment and simultaneously treated with FA and donepezil. The behavioral results revealed that chronic FA treatment reversed d-gal-induced memory impairment. Further, FA treatment inhibited d-gal-induced AChE activity and oxidative stress via increase of superoxide dismutase activity and reduced glutathione content, as well as decrease of malondialdehyde and nitric oxide levels. We also observed that FA significantly inhibits inflammation in the brain through reduction of NF-κB and IL-1β by enzyme-linked immunosorbent assay. Additionally, FA treatment significantly reduces the caspase-3 level in the hippocampus of d-gal-treated mice. Hematoxylin and eosin and Nissl staining showed that FA prevents neurodegeneration induced by d-gal. These findings showed that FA inhibits d-gal-induced AChE activity, oxidative stress, neuroinflammation and neurodegeneration, and consequently ameliorates memory impairment.

Topics: Acetylcholinesterase; Aging; Animals; Antioxidants; Brain; Caspase 3; Coumaric Acids; Disease Models, Animal; Donepezil; Galactose; Glutathione; Hippocampus; Indans; Interleukin-1beta; Male; Malondialdehyde; Memory Disorders; Mice; NF-kappa B; Nitric Oxide; Oxidative Stress; Piperidines; Superoxide Dismutase

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

Topics: Animals; Behavior, Animal; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Ethanol; Indans; Male; Maze Learning; Memory Disorders; Motor Activity; Nootropic Agents; Piperidines; Rats, Wistar; Reaction Time; Rivastigmine; Rotarod Performance Test; Spatial Memory; Time Factors

The cannabinoid system plays an important role in memory processes, many studies have indicated that cannabinoid receptor ligands have ability to modulate memory in rodents. A nonapeptide hemopressin (Hp) derived from rat brain, acts as a peptide antagonist or selective inverse peptide agonist of cannabinoid 1 (CB1) receptor. N-terminally extended forms of Hp isolated from mouse brain, (m)RVD-hemopressin(α) (RVD) and (m)VD-hemopressin(α) (VD) also bind CB1 receptor, however, as peptide agonists. Here, we investigated the roles of Hp, RVD, and VD on memory in mice using novel object recognition (NOR) and object location recognition (OLR) tasks. In normal young mice, intracerebroventricular (i.c.v.) infusion of Hp before training not only improved memory formation, but also prolonged memory retention in the tasks, these effects could be inhibited by RVD or VD at the same dose and intraperitoneal (i.p.) injection of a small molecule agonist of CB1 receptor WIN55, 212-2 15min before administration of Hp inhibited the memory-improving effect of Hp. In addition, under the same experimental conditions, i.c.v. RVD or VD displayed memory-impairing effects, which could be prevented by Hp (i.c.v.) or AM251 (i.p.), a small molecule antagonist of CB1 receptor. Infusion of amyloid-β (1-42) (Aβ1-42) 14days before training resulted in impairment of memory in mice which could be used as animal model of Alzheimer's disease (AD). In these mice, RVD or VD (i.c.v.) reversed the memory impairment induced by Aβ1-42, and the effects of RVD and VD could be suppressed by Hp (i.c.v.) or AM251 (2mg/kg, i.p.). Separate administration of Hp had no effect in Aβ1-42-treated mice. The above results suggested that Hp, RVD and VD, as CB1 receptor peptide ligands, may be potential drugs to treatment of the memory deficit-involving disease, just as AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Hemoglobins; Infusions, Intraventricular; Male; Memory Disorders; Mice; Morpholines; Naphthalenes; Oligopeptides; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology

Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine β-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH(+) cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.

Topics: Animals; Anisomycin; Dopamine beta-Hydroxylase; Electroshock; Hindlimb Suspension; Indoles; Male; Memory Consolidation; Memory Disorders; Mice, Knockout; Neurons; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Stress, Psychological

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1-0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5-20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.

Topics: Animals; Antipsychotic Agents; Cannabinoid Receptor Modulators; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Endocannabinoids; Excitatory Amino Acid Antagonists; Male; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Mice; Motor Activity; Oleic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Schizophrenia; Schizophrenic Psychology

The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZ-exposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.

Topics: Animals; Astrocytes; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cuprizone; Cyclin-Dependent Kinases; Demyelinating Diseases; Disease Models, Animal; Flavonoids; Gene Expression Regulation; Male; Memory Disorders; Memory, Short-Term; Mice, Inbred C57BL; Microglia; Myelin Sheath; Oligodendroglia; Piperidines; Protein Kinase Inhibitors; Stem Cells; Up-Regulation

Accumulation of amyloid-β (Aβ) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3β (GSK3β) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aβ and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3β. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3β signaling and contributes to subsequent down-regulation of Aβ and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aβ production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3β activity by increasing phosphorylation of GSK3β at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3β signaling which may contribute to down-regulation of Aβ and tau hyperphosphorylation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Disease Models, Animal; Donepezil; Drugs, Chinese Herbal; Glycogen Synthase Kinase 3; Hippocampus; Indans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphorylation; Piperidines; Signal Transduction; tau Proteins

Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain.

Topics: Adenine; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butyrates; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Encephalitis; Enzyme Inhibitors; Hippocampus; Hydrocarbons, Halogenated; Ibuprofen; Indans; Learning Disabilities; Male; Memory Disorders; Mice; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Piperidines

Rosmarinic acid (RA) is a natural phenol that exerts different biological activities, such as antioxidant activity and neuroprotective effects. In this study, we hypothesized that administration of RA (8, 16, and 32 mg/kg, p.o.) for 7 days would effect on scopolamine-induced cognitive dysfunction as an extensively used model of cognitive impairment. The rats were divided into 10 groups. The acquisition trial was done 1h after the last administration of RA. Animals were divided into control, RA (8, 16, and 32 mg/kg) and donepezil (2 mg/kg) treated controls, scopolamine, RA (8, 16, and 32 mg/kg), and donepezil (2 mg/kg) treated scopolamine groups. Memory impairment was induced by scopolamine treatment (1 mg/kg, i.p.) 30 min after the administration of RA, donepezil, or saline. Scopolamine administration caused cognition deficits in the PAL and memory paradigm. While orally RA administration (16 and 32 mg/kg) improved learning and memory in control rats, it reversed learning and memory deficits of scopolamine received groups. Administration of RA at the dose of 8 mg/kg did not alter cognitive function in control and scopolamine treated groups. The combination of anticholinesterase, neuroprotective, and antioxidant properties of RA may all be responsible for the observed effects. These results indicate the beneficial effects of subchronic RA administration in passive avoidance learning and memory in control rats as well as in a pharmacological model of cholinergic deficit which continue to expand the knowledge base in creating new treatment strategies for cognition deficits and dementia. Of course, further studies are warranted for clinical use of RA in the management of demented subjects.

Topics: Animals; Avoidance Learning; Cholinergic Antagonists; Cinnamates; Depsides; Donepezil; Indans; Male; Memory; Memory Disorders; Neuroprotective Agents; Piperidines; Rats, Wistar; Reaction Time; Rosmarinic Acid; Scopolamine

Alzheimer's disease (AD) is one of the major neurological diseases of the elderly. How to safely and effectively remove the toxic Aβ42 peptide through blood-brain barrier (BBB) is considered to be an effective method for the prevention and treatment of AD. The compounds whose molecule weight is less than 400 Da and the number of hydrogen bonding is less than 10 are more likely to permeate BBB. In our previous study, we have several small molecule compounds which are isolated from n-butanol (NB) extract of Alpinia oxyphylla that are similar with this kind of compounds This study explored the neuroprotective effects of the NB significantly protected against learning and memory impairments induced by Aβ(1-42) in Y-maze test, active avoidance test and Morris water maze test. Besides, NB (180 mg/kg, 360 mg/kg) was able to attenuate the neuronal damage and apoptosis in the frontal cortex and hippocampus in mice. In addition, the inhibition of β-secretase and the level of Aβ(1-42) are also involved in the action mechanisms of NB in this experimental model. This study provided an experimental basis for clinical application of A. oxyphylla Miq. in AD therapy.

Topics: 1-Butanol; Alpinia; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Avoidance Learning; Cerebral Cortex; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Glutathione; Indans; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Phytotherapy; Piperidines; Plant Extracts; Thiazolidinediones

Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Haloperidol; Isoindoles; Memory Disorders; Phencyclidine; Piperazines; Piperidines; Pyrimidines; Random Allocation; Rats, Long-Evans; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Urea

Lipopolysaccharide (LPS) induces neuroinflammation and memory deficit. Since polyamines improve memory in various cognitive tasks, we hypothesized that spermine administration reverses LPS-induced memory deficits in an object recognition task in mice. The involvement of the polyamine binding site at the N-methyl-D-aspartate (NMDA) receptor and cytokine production in the promnesic effect of spermine were investigated.. Adult male mice were injected with LPS (250 μg/kg, intraperitoneally) and spermine (0.3 to 1 mg/kg, intraperitoneally) or ifenprodil (0.3 to 10 mg/kg, intraperitoneally), or both, and their memory function was evaluated using a novel object recognition task. In addition, cortical and hippocampal cytokines levels were measured by ELISA four hours after LPS injection.. Spermine increased but ifenprodil decreased the recognition index in the novel object recognition task. Spermine, at doses that did not alter memory (0.3 mg/kg, intraperitoneally), reversed the cognitive impairment induced by LPS. Ifenprodil (0.3 mg/kg, intraperitoneally) reversed the protective effect of spermine against LPS-induced memory deficits. However, spermine failed to reverse the LPS-induced increase of cortical and hippocampal cytokine levels.. Spermine protects against LPS-induced memory deficits in mice by a mechanism that involves GluN2B receptors.

Topics: Analysis of Variance; Animals; Cytokines; Discrimination, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists; Exploratory Behavior; Lipopolysaccharides; Male; Memory Disorders; Mice; Piperidines; Recognition, Psychology; Spermine

Donepezil, a cholinesterase inhibitor, is a representative symptomatic therapy for Alzheimer's disease (AD). Recent studies have reported the anti-inflammatory effects of donepezil. However, limited studies that investigate its anti-inflammatory effect in AD have been reported. Considering the role of proinflammatory molecules and microglial activation in the pathogenesis of AD, the current study aimed to elucidate the effects of donepezil on microglial activation induced by amyloid deposition in transgenic mice. Our results showed that chronic treatment with donepezil significantly improved the cognitive function in the novel object recognition test and Morris water maze test in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice. We further demonstrated that these cognitive enhancements were related to the anti-inflammatory effect of donepezil. We found that donepezil could inhibit the expression of CD68, a specific marker of microglial activation, and reduce the release of proinflammatory cytokines including tumor necrosis factor-α and interleukin-1β. Immunohistochemistry and Congo red co-staining revealed that congophilic amyloid and activated microglia around plaques were also reduced by donepezil treatment. Enzyme-linked immunosorbent assay (ELISA) analysis showed that donepezil decreased insoluble Aβ40/Aβ42 and soluble Aβ40 levels. Moreover, donepezil reversed the impaired expression of insulin-degrading enzyme in the hippocampus of APP/PS1 mice. Our findings indicated that donepezil improves cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of microglial activation and release of proinflammatory cytokines.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain; Cytokines; Donepezil; Indans; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurites; Nootropic Agents; Peptide Fragments; Piperidines; Plaque, Amyloid; Presenilin-1; Random Allocation; Recognition, Psychology

Cannabinoid and endocannabinoid systems have been implicated in several physiological functions including modulation of cognition. In this study we evaluated the effects and interaction between fatty-acid amide hydrolase (FAAH) inhibitor URB597 and CB1 receptor agonist WIN55, 212-2 on memory using object recognition and passive avoidance learning (PAL) tests. Learning and memory impairment was induced by WIN 55, 212-2 administration (1mg/kg, i.p.) 30min before the acquisition trial. URB597 (0.1, 0.3 and 1mg/kg, i.p.) or SR141716A (1mg/kg, i.p.) was injected to rats 10min before WIN 55, 212-2 or URB597 respectively. URB597 (0.3 and 1mg/kg) but not 0.1mg/kg induced higher discrimination index (DI) in object recognition test and enhanced memory acquisition in PAL test. The cognitive enhancing effect of URB597 was blocked by a CB1 receptor antagonist, SR141716A which at this dose alone had no effect on cognition. WIN55, 212-2 caused cognition deficits in both tests. URB597 (0.3 and 1mg/kg) treatment could alleviate the negative influence of WIN 55, 212-2 on cognition and memory. These results indicate URB597 potential to protect against memory deficits induced by cannabinoid. Therefore, in combination with URB597 beneficial effects, this study suggests that URB597 has recognition and acquisition memory enhancing effects. It may also constitute a novel approach for the treatment of cannabinoid induced memory deficits and lead to a better understanding of the brain mechanisms underlying cognition.

Topics: Amidohydrolases; Animals; Benzamides; Benzoxazines; Carbamates; Learning; Male; Memory Disorders; Morpholines; Naphthalenes; Nootropic Agents; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Retention, Psychology; Rimonabant

Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis.

Topics: Animals; Brain Injuries; Dentate Gyrus; Disease Models, Animal; Donepezil; Female; Ganciclovir; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Neurogenesis; Piperidines; Spatial Learning; Valganciclovir

We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aβ were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease.

Topics: Aging; Alzheimer Disease; Animals; Cholinergic Agents; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Indans; Memory Disorders; Mice, Transgenic; Nootropic Agents; Piperidines; Quinolizines; Receptor, Muscarinic M1; Recognition, Psychology

Exposure to methamphetamine (meth) can produce lasting memory impairments in humans and rodents. We recently demonstrated that extended access meth self-administration results in novel object recognition (NOR) memory deficits in rats. Recognition of novelty depends upon intact perirhinal (pRh) cortex function, which is compromised by meth-induced downregulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors. NMDA receptors containing this subunit have a critical role in pRh long-term depression (LTD), one of the primary physiological processes thought to underlie object recognition memory. We hypothesized that meth-induced downregulation of GluN2B receptors would compromise pRh LTD, leading to loss of NOR memory. We found that meth self-administration resulted in an inability to induce pRh LTD following 1 Hz stimulation, an effect that was reversed with bath application of the NMDA receptor partial agonist D-cycloserine (DCS). In addition, pRh microinfusion of DCS restored meth-induced memory deficits. Furthermore, blockade of GluN2B-containing NMDA receptors with Ro 25-6981 prevented DCS restoration of pRh LTD in meth subjects. Thus, targeting pRh LTD may be a promising strategy to treat meth-induced cognitive impairment.

Topics: Amphetamine-Related Disorders; Animals; Central Nervous System Stimulants; Cycloserine; Excitatory Amino Acid Agents; Long-Term Synaptic Depression; Male; Memory Disorders; Methamphetamine; Phenols; Piperidines; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Self Administration; Tissue Culture Techniques

A series of [1,3]dioxolo[4,5-f]isoindolone derivatives were designed, synthesized and evaluated as inhibitors of acetylcholinesterases (AChE). Furthermore, their effects on memory impairment of mice induced by scopolamine were investigated with step-through test. The results suggested that most of the target compounds exhibited potential inhibition on AChE with IC50 values at micromolar range. Compounds I1 (IC50 value of 0.086 μmol · L(-1)) and I2 (IC50 value of 0.080 μmol · L(-1)) showed the strongest AChE inhibitory activity, which are equipotent to donepezil (IC50 value of 0.094 μmol · L(-1)). Moreover, compounds I1-I4 could improve the memory impairment induced by scopolamine in mice.

Topics: Animals; Cholinesterase Inhibitors; Dioxoles; Donepezil; Drug Design; Indans; Inhibitory Concentration 50; Isoindoles; Memory Disorders; Mice; Piperidines; Scopolamine

Memory impairment induced by ethanol in rats is a consequence of changes in the CNS that are secondary to impaired oxidative stress and cholinergic dysfunction. Treatment with antioxidants and cholinergic agonists are reported to produce beneficial effects in this model. Berberine, an isoquinoline alkaloid is reported to exhibit antioxidant effect and cholinesterase (ChE) inhibitor activity. However, no report is available on the influence of berberine on ethanol-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in ethanol-induced rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameter of oxidative stress and cholinesterase (ChE) activity as a marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Forty five days after ethanol treated rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., once a day for 45days) improved cognitive performance, and lowered oxidative stress and ChE activity in ethanol treated rats. In another set of experiments, berberine (100mg/kg) treatment during training trials also improved learning and memory, and lowered oxidative stress and ChE activity. Chronic treatment (45days) with vitamin C, and donepezil during training trials also improved ethanol-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In conclusion, the present study demonstrates that treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in ethanol treated rats.

Topics: Animals; Ascorbic Acid; Behavior, Animal; Berberine; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Ethanol; Glutathione; Hippocampus; Indans; Lipid Peroxidation; Male; Memory Disorders; Oxidative Stress; Piperidines; Rats

Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as "Spice" or "K2" to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of "Spice/K2", including JWH-081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH-081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of JWH-081 on pCaMKIV, pCREB, and pERK1/2 signaling events followed by long-term potentiation (LTP), hippocampal-dependent learning and memory tasks using CB1 receptor wild-type (WT) and knockout (KO) mice. Acute administration of JWH-081 impaired CaMKIV phosphorylation in a dose-dependent manner, whereas inhibition of CREB phosphorylation in CB1 receptor WT mice was observed only at higher dose of JWH-081 (1.25 mg/kg). JWH-081 at higher dose impaired CaMKIV and CREB phosphorylation in a time-dependent manner in CB1 receptor WT mice but not in KO mice and failed to alter ERK1/2 phosphorylation. In addition, SR treated or CB1 receptor KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio compared with vehicle or WT littermates. In hippocampal slices, JWH-081 impaired LTP in CB1 receptor WT but not in KO littermates. Furthermore, JWH-081 at higher dose impaired object recognition, spontaneous alternation and spatial memory on the Y-maze in CB1 receptor WT mice but not in KO mice. Collectively our findings suggest that deleterious effects of JWH-081 on hippocampal function involves CB1 receptor mediated impairments in CaMKIV and CREB phosphorylation, LTP, learning and memory in mice.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Cannabinoid Receptor Antagonists; Cannabinoids; CREB-Binding Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Indoles; Learning Disabilities; Long-Term Potentiation; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalenes; Phosphorylation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Space Perception; Synapses

Recent studies on Alzheimer's disease (AD) have focused on soluble oligomeric forms of amyloid-beta (Aβ oligomer, AβO) that are directly associated with AD-related pathologies, such as cognitive decline, neurodegeneration, and neuroinflammation. Donepezil is a well-known anti-dementia agent that increases acetylcholine levels through inhibition of acetylcholinesterase. However, a growing body of experimental and clinical studies indicates that donepezil may also provide neuroprotective and disease-modifying effects in AD. Additionally, donepezil has recently been demonstrated to have anti-inflammatory effects against lipopolysaccharides and tau pathology. However, it remains unknown whether donepezil has anti-inflammatory effects against AβO in cultured microglial cells and the brain in animals. Further, the effects of donepezil against AβO-mediated neuronal death, astrogliosis, and memory impairment have also not yet been investigated. Thus, in the present study, we examined the anti-inflammatory effect of donepezil against AβO and its neuroinflammatory mechanisms. Donepezil significantly attenuated the release of inflammatory mediators (prostaglandin E2, interleukin-1 beta, tumor necrosis factor-α, and nitric oxide) from microglia. Donepezil also decreased AβO-induced up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 protein and phosphorylation of p38 mitogen-activated protein kinase as well as translocation of nuclear factor-kappa B. We next showed that donepezil suppresses activated microglia-mediated toxicity in primary hippocampal cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In intrahippocampal AβO-injected mice, donepezil significantly inhibited microgliosis and astrogliosis. Furthermore, behavioral tests revealed that donepezil (2 mg/kg/day, 5 days, p.o.) significantly ameliorated AβO-induced memory impairment. These results suggest that donepezil directly inhibits microglial activation induced by AβO through blocking MAPK and NF-κB signaling and, in part, contributing to the amelioration of neurodegeneration and memory impairment.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Cells, Cultured; Donepezil; Hippocampus; Indans; Inflammation Mediators; Male; Memory Disorders; Mice; Mice, Inbred ICR; Microglia; p38 Mitogen-Activated Protein Kinases; Piperidines; Rats, Sprague-Dawley; Transcription Factor RelA

Donepezil (DP) is the major drug currently used for enhancing memory function in patients with Alzheimer's disease (AD), an action ascribed to the elevation of central cholinergic neurotransmission. However, there are indications that DP may protect neurons against injury through the prevention of free radical-mediated neuroinflammation that has been implicated in the pathology of AD. Thus, this study was carried out to examine the effect of DP on memory impairment and on biomarkers of oxidative stress induced by scopolamine (SC) and lipopolysaccharide (LP) in mice.Mice were treated with DP (0.5-4 mg/kg, i. p.) 30 min prior to i. p. injection of SC or LP once daily for 7 days before assessing for memory function utilizing the Y-maze paradigm and levels of biomarkers of oxidative stress using standard biochemical procedures.DP (0.5-2 mg/kg) significantly reversed the memory impairment produced by SC (1 mg/kg) or LP (250 µg/kg) in mice, indicating memory enhancing effect. The increased brain levels of malondialdehyde (MDA) evoked by SC (1 mg/kg) or LP (250 µg/kg), was significantly inhibited by DP (0.5-4 mg/kg), suggesting antioxidant property. Further, DP (0.5-4 mg/kg) significantly inhibited glutathione (GSH) depletion caused by SC (1 mg/kg) or LP (250 µg/kg) in mice brains, which suggest free radical scavenging property.These findings suggest that DP has antioxidant effect, which might be playing a significant role in its memory enhancing activity in mice. However, more detailed studies are necessary to confirm the relevance of this finding and its implications in clinical settings.

Topics: Animals; Antioxidants; Biomarkers; Donepezil; Free Radical Scavengers; Free Radicals; Glutathione; Indans; Lipopolysaccharides; Male; Malondialdehyde; Memory; Memory Disorders; Mice; Oxidative Stress; Piperidines; Scopolamine

Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B)-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2) signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII), synapse-associated protein 102 (SAP102) and Ras GTPase-activating protein (SynGAP) have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor) have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway.. Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9 ∼ 11%O2, 5.5 ∼ 6.5%CO2) for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist) administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) activation, which is responsible for neuroprotection.. These findings suggest that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of excessive NR2B expression accompanied by increased expression of ERK signaling cascade. The effect of NR2B in upregulating pERK1/2 maybe due, at least in part, to inactivation of CaMKII/SAP102/SynGAP signaling cascade.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Chronic Disease; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gene Expression Regulation; GTPase-Activating Proteins; Hippocampus; Hypercapnia; Hypoxia; Learning Disabilities; Lovastatin; Male; MAP Kinase Signaling System; Maze Learning; Membrane Microdomains; Memory Disorders; Neuropeptides; Nootropic Agents; Piperidines; Pulmonary Disease, Chronic Obstructive; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spatial Learning; Synaptosomes

Interactions between cannabinoid and glutamate systems have been demonstrated in some brain areas associated with mnemonic functions. This study investigates the effects of bilateral post-training intra-nucleus accumbens (NAc) shell administrations of glutamate NMDA receptor agents on memory impairment induced by cannabinoid CB1 receptor activation during a step-through inhibitory avoidance (IA) task. Our results showed post-training administration of ACPA (CB1 receptor agonist; 3 ng/side) impairs IA memory consolidation, whereas AM251 (CB1 receptor antagonist; 0.3, 3 and 30 ng/side), NMDA (0.3, 3 and 30 ng/side), and d-AP7 (NMDA receptor antagonist; 3, 30 and 300 ng/side) were ineffective. However, co-administration of AM251 (30 ng/side) or NMDA (30 ng/side) with ACPA (3 ng/side) prevented the memory-impairing effect of ACPA. Meanwhile, co-administration of NMDA (30 ng/side) and a subthreshold dose of ACPA (0.15 ng/side) decreased memory consolidation. Moreover, post-training microinjection of AM251 (30 ng/side) or d-AP7 (300 ng/side) prevented memory impairment induced by co-administration of subthreshold doses of NMDA and ACPA. The data indicated that NMDA receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the NAc shell.

Topics: 2-Amino-5-phosphonovalerate; Animals; Arachidonic Acids; Avoidance Learning; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Glutamic Acid; Male; Memory; Memory Disorders; Motor Activity; N-Methylaspartate; Nucleus Accumbens; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1

Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use. Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated, reconsolidation of memories of physiologically relevant social rewards has received little attention. Social play, the most characteristic social behaviour displayed by young mammals, is highly rewarding, illustrated by the fact that it can induce conditioned place preference (CPP). Here, we investigated the role of signalling mechanisms implicated in memory processes, including reconsolidation, namely glucocorticoid, mineralocorticoid, NMDA glutamatergic and CB1 cannabinoid receptors, in the reconsolidation of social play-induced CPP in rats. Systemic treatment with the glucocorticoid receptor antagonist mifepristone before, but not immediately after, retrieval disrupted the reconsolidation of social play-induced CPP. Mifepristone did not affect social play-induced CPP in the absence of memory retrieval. Treatment with the NMDA receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP. However, the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and CB1 cannabinoid receptor antagonists spironolactone and rimonabant, respectively. We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats. These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories.

Topics: Analysis of Variance; Animals; Cannabinoid Receptor Antagonists; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hormone Antagonists; Male; Memory Disorders; Mifepristone; Mineralocorticoid Receptor Antagonists; Neuroprotective Agents; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reward; Rimonabant; Social Behavior; Spironolactone

5-HT4 receptors (5-HT4R) are suggested to affect learning and memory processes. Earlier studies have shown that animals treated with 5-HT4R agonists, often with limited selectivity, show improved learning and memory with retention memory often being assessed immediately after or within 24 h after the last training session. In this study, we characterized the effect of pre-training treatment with the selective 5-HT4R agonist SSP-002392 on memory acquisition and the associated long-term memory retrieval in animal models of impaired cognition. Pre-training treatment with SSP-002392 (0.3 mg/kg, 1.5 mg/kg and 7.5 mg/kg p.o.) dose-dependently inhibited the cognitive deficits induced by scopolamine (0.5 mg/kg s.c.) in two different behavioral tasks: passive avoidance and Morris water maze. In the Morris water maze, spatial learning was significantly improved after treatment with SSP-002392 translating in an accelerated and more efficient localization of the hidden platform compared to scopolamine-treated controls. Moreover, retention memory was assessed 24 h (passive avoidance) and 72 h (Morris water maze) after the last training session of cognitive-impaired animals and this was significantly improved in animals treated with SSP-002392 prior to the training sessions. Furthermore, the effects of SSP-002392 were comparable to galanthamine hydrobromide. We conclude that SSP-002392 has potential as a memory-enhancing compound.

Topics: Animals; Anxiety; Avoidance Learning; Benzofurans; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Galantamine; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Nootropic Agents; Piperidines; Random Allocation; Receptors, Serotonin, 5-HT4; Scopolamine; Serotonin 5-HT4 Receptor Agonists

Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Attention Deficit and Disruptive Behavior Disorders; Behavior, Animal; Disease Models, Animal; Female; HEK293 Cells; Humans; In Vitro Techniques; Male; Maze Learning; Membrane Potentials; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperidines; Synapses

In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Aβ. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Aβ. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25-35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Aβ25-35 (10 µM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Aβ-induced nuclear translocation of Jacob was blocked upon application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Aβ25-35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Aβ25-35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) reversed these effects of Aβ25-35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved in Aβ pathology.

Topics: Amyloid beta-Peptides; Animals; Biguanides; Binding Sites; Cell Nucleus; Dendritic Spines; Exploratory Behavior; Hippocampus; Male; Memory Disorders; Mice; Nerve Tissue Proteins; Peptide Fragments; Piperidines; Polyamines; Receptors, N-Methyl-D-Aspartate; Spermidine; Synapses

Traumatic brain injury (TBI) is the leading cause of death in young adults in the United States, but there is still no effective agent for treatment. N-arachidonoylethanolamine (anandamide, AEA) is a major endocannabinoid in the brain. Its increase after brain injury is believed to be protective. However, the compensatory role of AEA is transient due to its rapid hydrolysis by the fatty acid amide hydrolase (FAAH). Thus, inhibition of FAAH can boost the endogenous levels of AEA and prolong its protective effect. Using a TBI mouse model, we found that post-injury chronic treatment with PF3845, a selective and potent FAAH inhibitor, reversed TBI-induced impairments in fine motor movement, hippocampus dependent working memory and anxiety-like behavior. Treatment with PF3845 inactivated FAAH activity and enhanced the AEA levels in the brain. It reduced neurodegeneration in the dentate gyrus, and up-regulated the expression of Bcl-2 and Hsp70/72 in both cortex and hippocampus. PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. Furthermore, PF3845 suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 post-TBI, suggesting a shift of microglia/macrophages from M1 to M2 phenotype. The effects of PF3845 on TBI-induced behavioral deficits and neurodegeneration were mediated by activation of cannabinoid type 1 and 2 receptors and might be attributable to the phosphorylation of ERK1/2 and AKT. These results suggest that selective inhibition of FAAH is likely to be beneficial for TBI treatment.

Topics: Amidohydrolases; Animals; Anxiety; Brain; Brain Injuries; Caspase 3; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Male; Memory Disorders; Mice, Inbred C57BL; Motor Activity; Neuroimmunomodulation; Neuroprotective Agents; Piperidines; Proto-Oncogene Proteins c-akt; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Recovery of Function

Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.

Topics: Animals; Brain Diseases; Calcium Channel Blockers; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Hippocampus; Homocysteine; Hyperhomocysteinemia; Indans; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Nifedipine; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Silver Staining; Tacrine

We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.

Topics: Aging; Animals; Donepezil; Drug Synergism; Flumazenil; GABA-A Receptor Agonists; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Naphthyridines; Nootropic Agents; Oxadiazoles; Piperidines; Rats; Scopolamine

The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable with the third trimester in human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB1R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB1R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively. N-Arachidonoyl phosphatidylethanolamine-phospholipase D (NAPE-PLD), glycerophosphodiesterase (GDE1), and CB1R protein expression were enhanced by transcriptional activation of the genes encoding NAPE-PLD, GDE1, and CB1R proteins, respectively. In addition, ethanol inhibited ERK1/2 and AKT phosphorylation. The blockade of CB1Rs before ethanol treatment at P7 relieved ERK1/2 but not AKT phosphorylation and prevented neurodegeneration. CB1R knock-out mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2 phosphorylation. The protective effects of CB1R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA/CB1R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.

Topics: Animals; Animals, Newborn; Arachidonic Acids; Brain; Cannabinoid Receptor Antagonists; Endocannabinoids; Ethanol; Female; Gene Expression Regulation, Developmental; Glycerides; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration; Nerve Tissue Proteins; Neuronal Plasticity; Neuroprotective Agents; Phospholipase D; Phosphoric Diester Hydrolases; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Synapses

This study investigated the role of H₁ and H₂ receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H₁ receptor, but not H₂, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

Topics: Animals; Anxiety; Benzothiazoles; Chlorpheniramine; Histamine H1 Antagonists; Histamine H2 Antagonists; Male; Maze Learning; Memory Disorders; Mice; Microinjections; Phenoxypropanolamines; Piperidines; Receptors, Histamine H1

Global cerebral ischemia followed by reperfusion, which leads to extensive neuronal damage, particularly the neurons in the hippocampal CA1 region. Apoptosis is one of the major mechanisms that lead to neuronal death after cerebral ischemia and reperfusion. The neuroprotective effects of remifentanil preconditioning against cerebral ischemia/reperfusion injury have been recently reported. Here we investigated whether remifentanil postconditioning exerts neuroprotective effects against global cerebral ischemia/reperfusion injury in rats and its potential mechanisms. Global cerebral ischemia was performed via 10 min of four-vessel occlusion. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells and expression of Bcl-2 and Bax in the hippocampal CA1 region were assessed after reperfusion. Morris water maze task was used to quantify spatial learning and memory deficits after reperfusion. We found remifentanil postconditioning markedly improved the spatial learning and memory as well as attenuated neuronal apoptosis in hippocampus caused by cerebral ischemia/reperfusion injury. In addition, remifentanil postconditioning enhanced the expression of anti-apoptotic gene Bcl-2 while suppressed the expression of pro-apoptotic gene Bax in hippocampal CA1 region. However, the neuroprotective effects of remifentanil postconditioning were abolished by pretreatment of the PI3K inhibitor LY294002. The results suggest that remifentanil postconditioning exhibits neuroprotective effects against global cerebral ischemia/reperfusion injury in rats, and its mechanisms might involve inhibition of neuronal apoptosis through the PI3K pathway.

Topics: Animals; Apoptosis; Brain Ischemia; Hippocampus; Male; Maze Learning; Memory Disorders; Neurons; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Signal Transduction; Time Factors

The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor-like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP-R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP-R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event.

Topics: Adult; Amygdala; Animals; Anxiety; Conditioning, Psychological; Cues; Disease Models, Animal; Fear; Female; Gene Expression Regulation; Humans; Immobilization; Male; Memory Disorders; Memory, Long-Term; Mice; Mice, Inbred C57BL; Nerve Net; Nociceptin Receptor; Piperidines; Receptors, Opioid; Stress Disorders, Post-Traumatic

Altered cognitive function is a common feature of both the early and later stages of Parkinson's disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined.. The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC.. Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied.. PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats.. PFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.

Topics: Adenosine A2 Receptor Antagonists; Animals; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Dopamine; Indans; Male; Memory Disorders; Memory, Short-Term; Methamphetamine; Oxidopamine; Piperidines; Prefrontal Cortex; Purines; Rats; Rats, Sprague-Dawley

We explored the attenuating effects of NP-9 on β-amyloid (Aβ) aggregation and amyloid-induced toxicity. NP-9 is a recently reported monoamine oxidase B (MAO-B), and acetylcholinesterase (AChE) inhibitor. In the present study, we found that NP-9 inhibited AChE activity in a dose-dependent manner with a maximal inhibition dose of 8 mg/kg, i.p. It inhibited Aβ aggregation, observed through thioflavin-T assay (IC50=60 μM) and scanning electron microscopy (S.E.M.) (no fibril formation). NP-9 has shown marked protection against scopolamine and Aβ1-42-induced memory impairments. It also minimized neuronal loss and amyloid plaque deposition in the brains of Aβ1-42-induced mice model. Therefore, NP-9 could be a promising lead molecule for AD, with effects against MAO-B, AChE, Aβ aggregation, and Aβ1-42 induced toxicity.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Animals; Anthracenes; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Exploratory Behavior; Glutathione; Immunohistochemistry; Indans; Male; Maze Learning; Memory; Memory Disorders; Mice; Microscopy, Electron, Scanning; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Muscarinic Antagonists; Oxidation-Reduction; Peptide Fragments; Piperidines; Psychomotor Performance; Pyrazoles; Scopolamine; Tissue Fixation

The aim of the present study was to evaluate the effect of the monoaminergic stabilizer (-)-OSU6162 on spatial recognition memory. Male NMRI mice were tested in the object location model which is based on the animals' inherent interest to examine changes in their environment: The animals' propensity to explore relocated objects in relation to unaltered objects, presented in two different sessions (sample and trial), was studied. In a first series of experiments the effect of (-)-OSU6162 on natural forgetting was evaluated. With an inter-session interval (ISI) of 30 min or an hour, untreated mice spent longer time exploring the displaced object, but when the time between sessions was as long as 6 h, the mice did not identify the displaced object. However, using the 6 h ISI design we found that (-)-OSU6162 in doses up to 30 μmol/kg, given directly after the sample session, caused an increased interest for the displaced object. Twenty-four hours after administration, (-)-OSU6162 was still effective in facilitating identification of the displaced object. We also evaluated the effect of (-)-OSU6162 on scopolamine-induced memory deficits in this model - the two agents were given 30 min before the sample session and the ISI was one hour. Under these conditions scopolamine induced a deficit in object location memory and this effect was counteracted by (-)-OSU6162. The data from the present study suggest that (-)-OSU6162 prolongs object location memory in normal mice and reverses scopolamine-induced memory deficits. (-)-OSU6162 might be a valuable drug candidate for memory deficits and other cognitive impairments.

Topics: Animals; Discrimination, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Memory Disorders; Mice; Motor Activity; Neuroprotective Agents; Piperidines; Scopolamine; Time Factors

Cannabinoid type 2 (CB(2)) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)-a novel selective CB(2) agonist that lacks psychoactivity-on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)(1-40) fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ(1-40) fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB(2) receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease.

Topics: Amyloid beta-Peptides; Animals; Astrocytes; Behavior, Animal; Benzofurans; CA1 Region, Hippocampal; CD11b Antigen; Cognition; Glial Fibrillary Acidic Protein; Interleukin-1beta; Memory; Memory Disorders; Microglia; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2

Alzheimer's disease is characterized by a progressive decline in cognitive function and involves β-amyloid (Aβ) in its pathogenesis. To characterize cognitive deficits associated with Aβ accumulation, we analyzed PS1/APP mice overexpressing mutant presenilin-1 (PS1, M146L; line 6.2) and amyloid precursor protein (APP, K670N/M671L; line Tg2576), a mouse model of Alzheimer's disease with accelerated Aβ production. Age-dependent changes in working and spatial memory behaviors were investigated using Y-maze and Morris water maze tasks, respectively, in female PS1/APP mice at ages of 2, 4, 6, and 12 months. Significant deficits in working and spatial memory were observed from 4 and 6 months of age, respectively. Acute single-dose administrations of memantine, a low-to-moderate-affinity N-methyl-d-aspartate (NMDA) antagonist, showed improvements in working memory deficits at 4 months of age, whereas donepezil, an acetylcholinesterase (AChE) inhibitor, did not. However, both drugs improved spatial memory dysfunction at 6 months of age at therapeutically relevant doses. No age-related dramatic changes were observed in expression levels of several proteins relating to memory dysfunction and also the mechanisms of donepezil and memantine in the cerebral cortex of PS1/APP mice until 6 months of age. Taken together, these results suggest dysfunctions in cholinergic and/or glutamatergic transmissions may be involved in the cognitive deficits associated with Aβ toxicity. Since donepezil and memantine have been widely used for treating patients of Alzheimer's disease, these results also suggest that cognitive deficits in PS1/APP mice assessed in the Y-maze and Morris water maze tasks are a useful animal model for evaluating novel Alzheimer's disease therapeutics.

Topics: Alzheimer Disease; Animals; Brain; Cholinesterase Inhibitors; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Donepezil; Female; Indans; Maze Learning; Memantine; Memory; Memory Disorders; Mice; Mice, Transgenic; Nootropic Agents; Piperidines; Receptors, AMPA

Histamine H(3) receptor antagonists have been considered as potential drugs to treat central nervous system diseases. However, whether these drugs can inhibit epileptogenesis remains unclear. This study aimed to investigate the effects of thioperamide, a selective and potent histamine H(3) receptor antagonist, on the seizure development and memory impairment induced by pentylenetetrazole (PTZ)-kindling epilepsy in rats.. Chemical kindling was elicited by repeated intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35 mg/kg) once every 48 hours for 12 times, and seizure activity of kindling was recorded for 30 minutes. Control rats were ip injected with saline instead of PTZ. Morris water maze was used to evaluate the spatial memory. Phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) was tested by Western blotting in hippocampus.. Intracerebroventricular (icv) injections with thioperamide (10 µg, 20 µg) 30 minutes before every PTZ injections, significantly prolonged the onset of PTZ-kindling and inhibited the seizure stages. PTZ-kindling seizures led to the impairment of spatial memory in rats, and thioperamide ameliorated the impairment of spatial learning and memory. Compared to non-kindling rats, there was a significant decrease in p-CREB level in hippocampus of the PTZ-kindling rats, which was reversed by thioperamide.. Thioperamide plays a protective role in seizure development and cognitive impairment of PTZ-induced kindling in rats. The protection of thioperamide in cognitive impairment is possibly associated with the enhancement of CREB-dependent transcription.

Topics: Animals; Anticonvulsants; Cyclic AMP Response Element-Binding Protein; Histamine H3 Antagonists; Kindling, Neurologic; Male; Memory Disorders; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Synaptic Transmission

Like emotional symptoms such as anxiety, modulations in working memory are among the frequently-reported but controversial psychiatric symptoms associated with nicotine (NC) administration. In the present study, repeated NC-induced modulations in working memory, along with concurrently-observed anxiety-related behavioral alterations, were investigated in mice, and compared with the effects of a typical cognition-impairing stressor, immobilization stress (IM). Furthermore, considering the structural and functional contributions of brain cannabinoid (CB) receptors in NC-induced psychiatric symptoms including emotional symptoms, the interactive effects of brain CB receptor ligands (CB ligands) and NC and/or IM on the working memory- and anxiety-related behaviors were examined.. Statistically significant working memory impairment-like behavioral alterations in the Y-maze test and anxiety-like behavioral alterations in the elevated plus-maze (EPM) test were observed in the groups of mice treated with 0.8 mg/kg NC (subcutaneous (s.c.) 0.8 mg/kg treatment, 4 days) and/or IM (10 min treatment, 4 days). In the group of mice treated with NC plus IM (NC-IM group), an enhancement of the behavioral alterations was observed. Among the CB type 1 (CB1) antagonist AM 251 (AM), the non-selective CB agonist CP 55,940 (CP), and the CB1 partial agonist/antagonist virodhamine (VD), significant recovering effects were provided by AM (0.2-2.5 mg/kg) and VD (5 mg/kg) against the working memory impairment-like behaviors, whereas significant anxiolytic-like effects (recoveries from both attenuated percentage of entries into open arms and attenuated percentage of time spent on open arms) were provided by VD (1-10 mg/kg) and CP (2 mg/kg) against the anxiety-like behaviors.. Although working memory impairment- and anxiety-like behavioral alterations were commonly induced in the NC, IM, and NC-IM groups and the therapeutic involvement of CB receptors was shown, there were discrepancies in the types of effective CB ligands between the working memory- and anxiety-related behaviors. The differential involvements of CB receptor subtypes and indirectly activated neurotransmitter systems may contribute to these discrepancies.

Topics: Analysis of Variance; Animals; Anxiety; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred ICR; Nicotine; Piperidines; Pyrazoles; Receptors, Cannabinoid; Restraint, Physical

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus.

Topics: Animals; Brain Ischemia; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Death; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Donepezil; Gerbillinae; Hippocampus; Indans; Male; Maze Learning; Memory; Memory Disorders; Neurons; Neuroprotective Agents; Piperidines; Signal Transduction

Our previous studies demonstrate that a non-cholinesterase inhibitor (AChEI) compound catalpol, purified from a traditional Chinese medicinal herb Rehmannia glutinosa, could improve the symptoms and pathological changes in animal and cellular models of memory related neurodegenerative diseases. In this study, we compared catalpol with the most commonly used AChEI donepezil in respect to their mechanism of action on the neurodegenerative changes in an animal model induced by beta-amyloid (Aβ) plus glutamate receptor agonist. It was found that the model mice showed significant deficit in the learning ability and memory in Y maze avoidance test, and meanwhile both donepezil and catalpol greatly improve the learning ability and memory after 2 to 3 months' administration. At the selected doses, donepezil only partially raised the declined brain muscarinic acetylcholine receptor (M receptor) density and choline acetyltransferase (ChAT) activity resulting in these levels still lower than normal control, while catalpol completely retrieved these two parameters. ELISA revealed that catalpol, instead of donepezil, possessed the capability of elevating the declined brain BDNF level of the animal model. The ELISA results on the BDNF protein level was confirmed by quantitative RT-PCR measurement of BDNF mRNA in Aβ₂₅₋₃₅-treated primary culture of forebrain neurons. In combination with our previous work, we think the neuroprotective effects of donepezil and catalpol are mediated through different mechanisms. Since BDNF has been proved to be an important intrinsic factor in protecting neurodegenerative diseases, catalpol may be a hopefully effective compound against neurodegenerative changes induced by Aβ and glutamate receptor agonist.

Topics: Amyloid beta-Peptides; Animals; Cells, Cultured; Donepezil; Excitatory Amino Acid Agonists; Female; Indans; Iridoid Glucosides; Memory Disorders; Mice; Mice, Inbred ICR; Peptide Fragments; Piperidines; Protein Binding; Random Allocation; Receptors, Glutamate

The aim of the present study is to investigate the status of proinflammatory cytokine in the brain of intracerebroventricular (i.c.v.) okadaic acid (OKA) induced memory impaired rat.. OKA (200 ng) intracerebroventricular (i.c.v.) was administered in rats. Memory was assessed by Morris water maze test. Biochemical marker of neuroinflammation (TNF-α, IL-β), total nitrite, mRNA (RT PCR) and protein expression (WB) of iNOS and nNOS were estimated in rat brain areas.. OKA caused memory-impairment in rats with increased expression of proinflammatory cytokine TNF-α and IL-1β and total nitrite in brain regions hippocampus and cortex. The expression of mRNA and protein of iNOS was increased while; the expressions were decreased in case of nNOS. Pretreatment with antidementic drugs donepezil (5 mg/kg, p.o.) and memantine (10 mg/kg, p.o) for 13 days protected i.c.v. OKA induced memory impairment and changes in level of TNF-α, IL-β, total nitrite and expressions of iNOS and nNOS in OKA treated rat.. This study suggests that neuroinflammation may play a vital role in OKA induced memory impairment.

Topics: Animals; Behavior, Animal; Biomarkers; Blotting, Western; Donepezil; Excitatory Amino Acid Antagonists; Indans; Inflammation; Injections, Intraventricular; Interleukin-1beta; Male; Maze Learning; Memantine; Memory Disorders; Motor Activity; Nitrate Reductase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Nootropic Agents; Okadaic Acid; Piperidines; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species; RNA, Messenger; Tumor Necrosis Factor-alpha

Aging-associated cognitive impairment is an important health care issue since individuals with mild cognitive impairment are more likely to develop Alzheimer's disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment associated with aging were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70, and 140 mg/kg exerted an improved effect on the learning and memory impairment in aged rats. Subsequently, GHE afforded a beneficial action on eradication of free radicals without influence on the activity of glutathione peroxidase and superoxide dismutase. GHE treatment enhanced the expression levels of nerve growth factor. Meanwhile, proliferation of neural progenitor cells was elevated in hippocampus after treatment with GHE. Taken together, neurogenic niche improvement could be involved in the mechanism underlying neuroprotection of GHE against aging-associated cognitive impairment. These findings suggested that GHE might be a potential agent as cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease or treatment of aging-associated cognitive impairment.

Topics: Aging; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glutathione Peroxidase; Gossypium; Hippocampus; Indans; Learning Disabilities; Male; Malondialdehyde; Maze Learning; Memory Disorders; Nerve Growth Factor; Phosphopyruvate Hydratase; Phytotherapy; Piperidines; Plant Preparations; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Reaction Time; Superoxide Dismutase

Amyloid beta (Aβ) is believed to be responsible for the synaptic failure that occurs in Alzheimer's disease (AD), but there is little known about the functional impact of Aβ on intrinsic neuronal properties. Here, the cellular effect of Aβ-induced neurotoxicity on the electrophysiological properties of CA1 pyramidal neurons and the mechanism(s) of neuroprotection by CB1 cannabinoid receptor activation was explored.. A combination of behavioural, molecular and electrophysiological approaches was used.. Bilateral injections of the Aβ peptide fragment (1-42) into the prefrontal cortex caused a significant impairment in the retention and recall capability in the passive avoidance tasks and significantly increased the level of active caspase-3 in the hippocampus. Whole-cell patch clamp recordings revealed a significant reduction in the intrinsic action potential (AP) frequency and an increase in the discharge irregularity in the absence of synaptic inputs in Aβ treated group. Aβ treatment induced also significant changes in both the spontaneous and evoked neuronal responses. However, co-treatment with ACEA, a CB1 receptor agonist, preserved almost the normal intrinsic electrophysiological properties of pyramidal cells.. In vivo Aβ treatment altered significantly the intrinsic electrophysiological properties of CA1 pyramidal neurons and the activation of CB1 cannabinoid receptors exerted a strong neuroprotective action against Aβ toxicity.

Topics: Action Potentials; Amyloid beta-Peptides; Animals; Avoidance Learning; Behavior, Animal; Benzoxazines; CA1 Region, Hippocampal; Calcium; Caspase 3; Electrophysiological Phenomena; Enzyme Activation; Male; Memory Disorders; Morpholines; Naphthalenes; Neuroprotective Agents; Patch-Clamp Techniques; Peptide Fragments; Piperidines; Pyramidal Cells; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Brain; Calcium; Calcium-Binding Proteins; Cell Survival; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Egtazic Acid; Enzyme Inhibitors; Glycoproteins; Humans; Indans; Isoxazoles; Ligands; Maze Learning; Memory Disorders; Metalloproteases; Mice; Mice, Transgenic; Microfilament Proteins; Mutation; Neuroblastoma; Nootropic Agents; Panax; Peptide Fragments; Phytotherapy; Piperidines; Plant Proteins; Presenilin-1; Propionates; Protein Binding; Receptors, Lysophosphatidic Acid; Signal Transduction; Time Factors; Transfection

The present study has been designed to investigate the potential role of CCR-2 chemokine receptor in ischemic preconditioning as well as postconditioning induced reversal of ischemia-reperfusion injury in mouse brain. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using elevated plus-maze test and Morris water maze test. Rota rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min were employed to elicit ischemic preconditioning of brain, while three episodes of bilateral carotid artery occlusion for 10s and reperfusion of 10s immediately after the completion of were employed to elicit ischemic postconditioning of brain. Both prior ischemic preconditioning as well as ischemic postconditioning immediately after global cerebral ischemia prevented markedly ischemia-reperfusion-induced cerebral injury as measured in terms of infarct size, loss of memory and motor coordination. RS 102895, a selective CCR-2 chemokine receptor antagonist, attenuated the neuroprotective effect of both the ischemic preconditioning as well as postconditioning. It is concluded that the neuroprotective effect of both ischemic preconditioning as well as ischemic postconditioning may involve the activation of CCR-2 chemokine receptors.

Topics: Animals; Benzoxazines; Brain; Brain Ischemia; Cerebral Infarction; Female; Ischemic Postconditioning; Ischemic Preconditioning; Male; Maze Learning; Memory; Memory Disorders; Mice; Motor Activity; Piperidines; Receptors, CCR2; Reperfusion Injury

Central cholinergic system is involved in regulation of memory and disturbances in these results in memory loss. Previously, we examined the effect of okadaic acid, OKA (200ng, i.c.v.) on memory impairment and mitochondrial dysfunction in rats. In the present study, we investigated effect of OKA (i.c.v) on cholinergic function by observing acetylcholine level (ACh), acetylcholinestrase (AChE) activity, and mRNA expression of acetylcholinestrase and α7nicotinic receptor (α7-nAChR) as a cholinergic markers in brain areas (cerebellum, striatum cortex and hippocampus). In present work OKA, caused a significant decrease in acetylcholine level, acetylcholinestrase activity and mRNA expression of acetylcholinestrase and α7-nicotinic receptor in rat but these changes were mainly observed in cortex and hippocampus. Further, histopathological study by cresyl violet staining showed neuronal loss in cortex and hippocampus after OKA administration indicating neurotoxicity. Pretreatment with anti-dementic drugs donepezil (AChE inhibitor; 5mg/kg, p.o) and memantine (NMDA receptor antagonist; 10mg/kg, p.o) daily for 13 day prevented cholinergic dysfunction and neuronal loss in cortex and hippocampus of OKA treated rat. Daily per se treatment for 13 day with donepezil decreased acetylcholinestrase activity and increased mRNA expression of acetylcholinestrase and α7-nicotinic receptor. Whereas, per se treatment with memantine daily for 13 day did not affect acetylcholinestrase activity, mRNA expression of acetylcholinestrase and α7-nicotinic receptor. Findings of this work shows that OKA (i.c.v.), apart from memory impairment and mitochondrial dysfunction, as our previous study showed, also induced cholinergic dysfunction and neuronal loss, which can be addressed by antidementic drugs like donepezil and memantine.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Biomarkers; Donepezil; Gene Expression Regulation; Hippocampus; Indans; Male; Memantine; Memory Disorders; Motor Activity; Neurons; Neurotoxins; Okadaic Acid; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; RNA, Messenger

Naringenin is a flavone flavonoid possessing antidiabetic, antioxidant and memory improving effects. Therefore, we studied the influence of naringenin against type-2 diabetes-induced memory dysfunction in rats. Type-2 diabetes was induced by high-fat diet and high-fat emulsion for two weeks and a low dose of streptozotocin (35 mg/kg). The memory deficit was assessed by using a novel object recognition paradigm. The changes in oxidative markers and cholinesterase (ChE) levels were evaluated in the hippocampal region. After confirmation of diabetes, naringenin (50mg/kg) treatment was given to animals as a preventive and in another set of experiments naringenin (25 and 50mg/kg) or pioglitazone (5mg/kg) or donepezil (3mg/kg) treatments were started after long-standing diabetes (4 weeks after confirmation). Both the treatment schedules show significant protection and improvement in cognitive behavior against diabetes-induced memory dysfunction and biochemical changes. Also, treatment with pioglitazone and donepezil improved memory performance in rats. Naringenin was found to decrease oxidative stress by depleting elevated lipid peroxide and nitric oxide and elevating reduced glutathione levels. Cholinergic function was improved by naringenin through the inhibition of elevated ChE activity. In conclusion, the present study suggests that naringenin acts as an antioxidant and ChE inhibitor against type-2 diabetes-induced memory dysfunction.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Cholinesterase Inhibitors; Cholinesterases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Donepezil; Estrogen Antagonists; Fat Emulsions, Intravenous; Flavanones; Glutathione; Hypoglycemic Agents; Indans; Lipid Peroxidation; Male; Memory Disorders; Nitric Oxide; Parasympathetic Nervous System; Pioglitazone; Piperidines; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Thiazolidinediones

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dystonia; Female; Humans; Indans; Memory Disorders; Piperidines; Postural Balance; Sensation Disorders

The rhizome of Codonopsis lanceolata (family Campanulaceae), which contains lancemaside A as a main constituent, has been used as herbal medicine to treat inflammation, insomnia, and hypomnesia. Lancemaside A and echinocystic acid, which is its metabolite by intestinal microflora, potently inhibited acetylcholinesterase activity in a dose-dependent manner, with IC₅₀ value 13.6 μM and 12.2 μM, respectively. Its inhibitory potency is comparable with that of donepezil (IC₅₀=10.9 μM). Lancemaside A and echinocystic acid significantly reversed scopolamine-induced memory and learning deficits on passive avoidance task. Lancemaside A orally administered 5h before treatment with scopolamine reversed scopolamine-induced memory and learning deficits more potently than one orally administered 1h before. Echinocystic acid more potently reversed it than lancemaside A. Lancemaside A and echinocystic acid significantly reversed scopolamine-induced memory and learning deficits on the Y-maze and Morris water maze tasks. Lancemaside A and echinocystic acid also increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (p-CREB). Based on these findings, orally administered lancemaside A may be metabolized to echinocystic acid, which may be absorbed into the blood and ameliorate memory and learning deficits by inhibiting AChE activity and inducing BDNF and p-CREB expressions.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Brain-Derived Neurotrophic Factor; Cholinesterase Inhibitors; Codonopsis; Cyclic AMP Response Element-Binding Protein; Donepezil; Dose-Response Relationship, Drug; Indans; Intestinal Mucosa; Intestines; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred ICR; Oleanolic Acid; Phytotherapy; Piperidines; Plant Extracts; Rhizome; Scopolamine

Brain insulin receptors (IRs) have been suggested as an important regulatory factor for cognitive functions but the involvement of IR signaling in memory deficit associated with neurodegenerative conditions is not yet explored. In the present study, IR gene expression was studied by RT-PCR and signaling pathways by immunoblotting in CA1, DG and CA3 subregions of hippocampus in intracerebroventricular (ICV) administered streptozotocin (STZ, 3mg/kg twice) induced memory deficit model in rat. The effect of pre- and post-treatment of donepezil (5mg/kg po) and melatonin (20mg/kg po) on signaling pathways were studied. Effect of LY294002 (ICV), a PI3 Kinase inhibitor, was also investigated on memory functions and Akt phosphorylation. An increased IR expression (both gene and protein), phosphorylation of Shc, Erk1/2, IRS-1 and Akt in CA1 and CA3 region of P2M fraction was observed after training as compared to control. STZ treated rats showed memory deficit and significant decrease in IR expression, phosphorylation of IRS-1 and Akt only in CA3 region as compared to trained group which were reversed by pre and post-treatment of melatonin but donepezil was effective only against memory deficit. LY294002 (3mM) treatment showed delayed learning and decrease in Akt phosphorylation. This study suggests that IR expression and its signaling pathways in hippocampal CA1 and CA3 regions are involved in memory functions and STZ (ICV) induced memory deficit. Hippocampal IR system might be playing an important role in regulation of memory functions, however only IR/IRS-1/Akt pathway in CA3 region is associated with STZ induced memory deficit.

Topics: Animals; Blood Glucose; Chromones; Disease Models, Animal; Donepezil; Gene Expression; Hippocampus; Indans; Infusions, Intraventricular; Male; Maze Learning; Melatonin; Memory; Memory Disorders; Morpholines; Nootropic Agents; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Signal Transduction; Streptozocin

Memory impairment induced by streptozotocin in rats is a consequence of changes in CNS that are secondary to chronic hyperglycemia, impaired oxidative stress, cholinergic dysfunction, and changes in glucagon-like peptide (GLP). Treatment with antihyperglycemics, antioxidants, and cholinergic agonists are reported to produce beneficial effect in this model. Berberine, an isoquinoline alkaloid is reported to exhibit anti-diabetic and antioxidant effect, acetylcholinesterase (AChE) inhibitor, and increases GLP release. However, no report is available on influence of berberine on streptozotocin-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., twice daily, 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. In another set of experiment, berberine (100mg/kg) treatment during training trials also improved learning and memory, lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C or metformin, and donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or choline esterase activity. In conclusion, the present study demonstrates treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in diabetic rats.

Topics: Acetylcholine; Administration, Oral; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Berberine; Blood Glucose; Body Weight; Brain; Cholinesterase Inhibitors; Cholinesterases; Diabetes Mellitus, Experimental; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Exploratory Behavior; Glutathione; Hypoglycemic Agents; Indans; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Metformin; Piperidines; Rats; Rats, Wistar

Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.

Topics: Animals; Azetidines; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Inverse Agonism; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Oxadiazoles; Piperidines; Protein Binding; Pyrazoles; Receptor, Cannabinoid, CB1; Scopolamine

Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB(1) antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆(9)-tetrahydrocannabinol (THC), the primary constituent in cannabis.. Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation in hippocampal and cerebellar tissue from THC-dependent mice.. Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity in cerebellar, but not in hippocampal, membranes.. The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.

Topics: Animals; Dose-Response Relationship, Drug; Dronabinol; Male; Marijuana Abuse; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Piperidines; Pyrazoles; Rimonabant; Spatial Behavior; Substance Withdrawal Syndrome

Similar to patients with Alzheimer's disease (AD), dogs exhibit age-dependent cognitive decline, amyloid-β (Aβ) pathology, and evidence of cholinergic hypofunction. The present study sought to further investigate the role of cholinergic hypofunction in the canine model by examining the effect of the cholinesterase inhibitors phenserine and donepezil on performance of two tasks, a delayed non-matching-to-position task (DNMP) designed to assess working memory, and an oddity discrimination learning task designed to assess complex learning, in aged dogs. Phenserine (0.5 mg/kg; PO) significantly improved performance on the DNMP at the longest delay compared to wash-out and partially attenuated scopolamine-induced deficits (15 μg/kg; SC). Phenserine also improved learning on a difficult version of an oddity discrimination task compared to placebo, but had no effect on an easier version. We also examined the effects of three doses of donepezil (0.75, 1.5, and 6 mg/kg; PO) on performance of the DNMP. Similar to the results with phenserine, 1.5 mg/kg of donepezil improved performance at the longest delay compared to baseline and wash-out, indicative of memory enhancement. These results further extend the findings of cholinergic hypofunction in aged dogs and provide pharmacological validation of the canine model with a cholinesterase inhibitor approved for use in AD. Collectively, these studies support utilizing the aged dog in future screening of therapeutics for AD, as well as for investigating the links among cholinergic function, Aβ pathology, and cognitive decline.

Topics: Aging; Analysis of Variance; Animals; Behavior, Animal; Cholinergic Antagonists; Cholinesterase Inhibitors; Discrimination, Psychological; Disease Models, Animal; Dogs; Donepezil; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Indans; Learning Disabilities; Male; Memory Disorders; Neuropsychological Tests; Odorants; Physostigmine; Piperidines; Scopolamine

Effect of administration of selective N-methyl-D-aspartate (NMDA) receptor antagonist Ro 25-6981 on learning and memory in a dose which is known to stimulate neoneurogenesis was assessed in adult rats with different abilities to formation of spatial skills in different time periods after the antagonist injection. Wistar male rats were trained to find hidden platform in the Morris water maze for 5 consecutive days. Rats' learning ability for spatial skill formation was evaluated depending on platform speed achievements. In re-training sessions (cues and platform location changed), it was found that all rats received Ro 25-6981 13 days before the re-training demonstrated impaired spatial memory. At the same time the inhibitor injected 29 days before re-training selectively facilitated the formation of spatial skill in animals with initially low learning abilities.

Topics: Animals; Dose-Response Relationship, Drug; Male; Maze Learning; Memory; Memory Disorders; Neurogenesis; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Time Factors

The present study was planned to evaluate the cholinergic influence on mitochondrial activity and neurodegeneration associated with impaired memory in intracerebroventricular (ICV) streptozotocin (STZ) treated rats. STZ (3mg/kg), administered ICV twice with an interval of 48h between the two doses, showed significant impairment in spatial memory tested by water maze test 14 days after first dose without altering blood glucose level and locomotor activity. Animals were sacrificed on 21st day of ICV administration. STZ significantly increased malondialdehyde (MDA), reactive oxygen species (ROS), Ca(2+) ion influx, caspase-3 activity and decreased glutathione (GSH) level. Acetylcholinesterase inhibitors tacrine and donepezil (5mg/kg, PO) pretreatment significantly prevented STZ induced memory deficit, oxidative stress, Ca(2+) influx and caspase-3 activity. Carbachol, a muscarinic cholinergic agonist (0.01mg/kg, SC) did not show any significant effect on ROS generation, Ca(2+) ion influx and caspase-3 activity. While nicotinic cholinergic agonist, nicotine, significantly attenuated ICV STZ induced mitochondrial dysfunction and caspase-3 activity. The results indicate that instead of muscarinic receptors nicotinic receptors may be involved in neuroprotection by maintaining mitochondrial functions.

Topics: Analysis of Variance; Animals; Blood Glucose; Brain; Calcium; Caspase 3; Cell Death; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Glutathione; Indans; Injections, Intraventricular; Male; Malondialdehyde; Maze Learning; Memory Disorders; Mitochondria; Motor Activity; Neurons; Nicotine; Piperidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Nicotinic; Streptozocin; Tacrine

The 5-hydroxytryptamine(6) (5-HT(6)) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT(6) antagonists compound (CMP) X and CMP Y and the reference 5-HT(6) antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer's disease, AD) was used as a positive reference compound. First, effects of the 5-HT(6) antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT(6) antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT(6) antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine. Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT(6) antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT. In conclusion, the 5-HT(6) antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT(6) receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.

Topics: Animals; Cholinesterase Inhibitors; Donepezil; Exploratory Behavior; Guanidines; Indans; Male; Maze Learning; Memory Disorders; Nootropic Agents; Piperidines; Rats; Rats, Wistar; Recognition, Psychology; Scopolamine; Serotonin Antagonists; Sulfonamides

SuHeXiang Wan (SHXW), a Chinese traditional medicine has been used orally for the treatment of seizures, infantile convulsion, stroke and so forth. Previously, we reported the effects of modified SHXW essential oil mixture of the fragrance containing herbs on the sedative effect, anticonvulsant property and antioxidative activity after fragrance inhalation.. This study was undertaken to evaluate beneficial effects of a modified recipe of SHXW (termed as KSOP1009) consisting of a ethanol extract of 8 herbs including resin of Liquidambar orientalis Miller, seed of Myristica fragrans Houtt., rhizome of Cnidium officinale Makino, lumber of Santalum album L., fructus of Piper longum L., flower buds of Eugenia caryophyllata Merrill et Perry, pollen of Typha orientalis Presl., and root of Salvia miltiorrhiza Bunge in the neurodegenerative diseases such as Alzheimer's disease (AD). The transgenic mice of AD, Tg-APPswe/PS1dE9, were fed KSOP1009 or as a positive control, donepezil for 3 months from 4.5 months of age. Behavioral, immunological and ELISA analyses were used to assess memory impairment, Aβ accumulation and plaque deposition in the brain. Other in vitro works were performed to examine whether KSOP1009 inhibits the Aβ(1-42)-induced neurotoxicity in human neuroblastoma cell line, SH-SY5Y cells.. Intake of KSOP1009 improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of Tg-APPswe/PS1dE9 mice as much as that of donepezil treatment. KSOP1009 prevented the down-regulation of phospho-CREB and increased AKT phosphorylation in the AD-like brains. Moreover, KSOP1009 suppresses Aβ-induced apoptosis and ROS production in SH-SY5Y cells.. The present study suggests that KSOP1009 may develop as a therapeutic drug for treatment of AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Behavior, Animal; Brain; Cell Line, Tumor; Chemistry, Pharmaceutical; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Humans; Indans; Memory; Memory Disorders; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nootropic Agents; Peptide Fragments; Phosphorylation; Piperidines; Presenilin-1; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Time Factors

A wearable camera that takes pictures automatically, SenseCam, was used to generate images for rehearsal, promoting consolidation and retrieval of memories for significant events in a patient with memory retrieval deficits. SenseCam images of recent events were systematically reviewed over a 2-week period. Memory for these events was assessed throughout and longer-term recall was tested up to 6 months later. A written diary control condition followed the same procedure. The SenseCam review procedure resulted in significantly more details of an event being recalled, with twice as many details recalled at 6 months follow up compared to the written diary method. Self-report measures suggested autobiographical recollection was triggered by the SenseCam condition but not by reviewing the written diary. Emotional and social wellbeing questionnaires indicated improved confidence and decreased anxiety as a result of memory rehearsal using SenseCam images. We propose that SenseCam images provide a powerful boost to autobiographical recall, with secondary benefits for quality of life.

Topics: Cholinesterase Inhibitors; Cognitive Dysfunction; Cues; Donepezil; Environmental Monitoring; Female; Humans; Image Processing, Computer-Assisted; Indans; Medical Records; Memory Disorders; Memory, Episodic; Mental Recall; Microcomputers; Middle Aged; Nootropic Agents; Photography; Piperidines; Quality of Life; Self Report; Self-Help Devices

Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and α7 nicotinic receptor (α7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or α7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.

Topics: Acetylcholinesterase; Anesthetics, Inhalation; Animals; Blood Gas Analysis; Blotting, Western; Cholinesterase Inhibitors; Donepezil; Indans; Isoflurane; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Piperidines

Topics: Cholinesterase Inhibitors; Female; Humans; Indans; Male; Memory Disorders; Piperidines

Topics: Cholinesterase Inhibitors; Female; Humans; Indans; Male; Memory Disorders; Piperidines

Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclidine (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Previous studies have shown that sub-chronic PCP induces an enduring episodic memory deficit in female Lister Hooded rats in the novel object recognition (NOR) task. Here we show that positive modulation of AMPA receptor (AMPAR) mediated glutamate transmission alleviates cognitive deficits induced by sub-chronic PCP treatment. Female Lister hooded rats were treated sub-chronically with either vehicle (0.9% saline) or PCP (2mg/kg two doses per day for 7 days), followed by a 7 days washout period. 30 min prior to the acquisition trial of the NOR task animals were dosed with either vehicle, CX546 (10, 40 or 80 mg/kg) or CX516 (0.5, 2.5, 10, 40 or 80 mg/kg). Our results show that sub-chronic PCP treatment induced a significant decrease in the discrimination index (DI) and both ampakines CX546 and CX516 were able to reverse this disruption of object memory in rats in the novel object recognition task. These data suggest that positive AMPAR modulation may represent a mechanism for treatment of cognitive deficits in schizophrenia.

Topics: Analysis of Variance; Animals; Behavior, Animal; Brain Chemistry; Dioxoles; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Hallucinogens; Memory Disorders; Motor Activity; Phencyclidine; Piperidines; Rats; Receptors, AMPA; Recognition, Psychology; Video Recording; Visual Perception

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') abusers have persistent neuropsychiatric deficits including memory impairments after the cessation of abuse. On the other hand, cannabinoid CB(1) receptors have been implicated in learning/memory, and are highly expressed in the hippocampus, a region of the brain believed to have an important function in certain forms of learning and memory. In this study, we clarified the mechanism underlying the cognitive impairment that develops during MDMA withdrawal from the standpoint of the cannabinoid CB(1) receptors. Mice were administered MDMA (10 mg/kg, i.p.) once a day for 7 days. On the 7th day of withdrawal, a novel object recognition task was performed and the amount of cannabinoid CB(1) receptor protein was measured with western blotting. Recognition performance was impaired on the 7th day of withdrawal. This impairment was blocked by AM251, a cannabinoid CB(1) receptor antagonist, administered 30 min before the training trial or co-administered with MDMA. At this time, the level of cannabinoid CB(1) receptor protein increased significantly in the hippocampus but not the prefrontal cortex or striatum. This increase of CB(1) receptor protein in the hippocampus was also blocked by the co-administration of AM251. Furthermore, CB(1) receptor knockout mice showed no impairment of recognition performance on the withdrawal from MDMA. The impairment of recognition memory during withdrawal from MDMA may result from the activation of cannabinoid CB(1) receptors in the hippocampus.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Gene Expression Regulation; Hallucinogens; Hippocampus; Male; Memory Disorders; Mice; Mice, Knockout; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology; Substance Withdrawal Syndrome; Time Factors

This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats.. In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457.. The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism.. The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

Topics: Animals; Antipsychotic Agents; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorobenzenes; Imidazoles; Indoles; Memory Disorders; Phencyclidine; Piperidines; Quinolines; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reversal Learning; Schizophrenia; Sulfones

The mechanisms underlying the complex effects of acute stress on memory are incompletely understood. Previous work suggests that the activation of N-methyl-d-aspartate (NMDA) receptors specifically containing GluN2B subunits may underlie the disruptions in spatial memory retrieval caused by acute stress (Wong et al., 2007 PNAS 104:11471). The present experiments were designed to assess whether a similar mechanism is involved in recognition memory. Recognition memory retrieval was assessed in Sprague-Dawley rats using an object recognition test and an object-place recognition test, both of which rely on patterns of spontaneous exploration. Exposure to acute stress for 30 min immediately before the test phase of either test disrupted memory retrieval. Administration of the GluN2B-selective antagonist Ro25-6981 (6 mg/kg; i.p.) enhanced memory in the object recognition test regardless of whether animals were exposed to acute stress. In the object-place test, Ro25-6981 had no effect on memory retrieval in the absence of stress but promoted memory following acute stress. These data highlight the specific contributions made by GluN2B-containing NMDA receptors to recognition memory for different types of stimuli.

Topics: Animals; Excitatory Amino Acid Antagonists; Exploratory Behavior; Male; Memory Disorders; Neuropsychological Tests; Pattern Recognition, Visual; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Space Perception; Stress, Psychological; Time Factors

Okadaic acid (OKA) is a potent and selective inhibitor of protein phosphatases, PP2A and PP1. In the present study, we evaluated effect of intracerebroventricular (ICV) bilateral injection of OKA (100 and 200 ng) on memory function and oxidative stress in rats. ICV injection of OKA (200 ng) produced memory impairment as evidenced by no significant decrease in latency time to reach the hidden platform in water maze test. It produced increase in malondialdehyde (MDA), nitrite level, reactive oxygen species (ROS) generation, mitochondrial calcium ion [Ca(2)](i) level and decreased glutathione (GSH) level in rat brain areas, indicating oxidative stress. Furthermore, we evaluated the effect of anti-dementia drugs memantine, a NMDA antagonist, and donepezil, a cholinesterase inhibitor, on OKA ICV induced memory impairment. Administration of memantine (10 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 13 days starting from the OKA injection improved performance in memory tests and also significantly restored GSH, MDA, nitrite levels, ROS generation and [Ca(2+)](i) level. This study demonstrates that the clinically used anti-dementic drugs are effective in OKA induced free radical generation and memory impairment in rats. Thus, OKA ICV induced memory impairment in rat appeared as a useful test model to screen anti-dementia drugs.

Topics: Animals; Brain; Calcium Signaling; Cholinesterase Inhibitors; Dementia; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glutathione; Indans; Injections, Intraventricular; Male; Malondialdehyde; Maze Learning; Memantine; Memory; Memory Disorders; Neuropsychological Tests; Nitrites; Okadaic Acid; Oxidative Stress; Piperidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Treatment Outcome

Episodic memory is the capacity to recall an event in time and place (What? Where? When?). Impaired episodic memory is a debilitating cognitive symptom in schizophrenia but is poorly controlled by currently available antipsychotic drugs. Consistent with glutamatergic abnormality in schizophrenia, the NDMA receptor antagonist, phencyclidine (PCP), induces persistent 'schizophrenia-like' symptoms including memory deficits in humans and rodents and is widely used as an animal model of the disorder. However, in contrast to humans, PCP and PCP withdrawal-induced memory deficits in rodents are reversed by antipsychotic drugs such as clozapine. One possible explanation is that the memory tasks used in animal studies do not simultaneously test the What? Where? When? components that characterize episodic memory in human tasks. We investigated whether subchronic PCP withdrawal disrupts memory in rats in a task that requires simultaneous integration of memory for object, place and context. Rats learn to discriminate objects under specific spatial and contextual conditions analogous to the What? Where? When? components of human episodic memory. We found that PCP withdrawal impaired performance on this task and that the atypical antipsychotic drug clozapine did not reverse this impairment. However the acetylcholinesterase inhibitor (AChEI) donepezil, which has been shown to improve episodic memory in humans did reverse the effect of PCP. This suggests that PCP withdrawal disruption of object-place-context recognition in rats may prove to be a useful model to investigate episodic memory impairment in schizophrenia and supports the suggestion that AChEIs could prove to be a useful pharmacological strategy to specifically treat episodic memory problems in schizophrenia.

Topics: Animals; Clozapine; Donepezil; Indans; Male; Memory Disorders; Memory, Episodic; Phencyclidine; Piperidines; Rats; Substance Withdrawal Syndrome

Previous studies of rats with bilateral vestibular deafferentation (BVD) have demonstrated spatial memory deficits, suggesting adverse effects on the hippocampus. However, the longest post-operative time interval that has been studied was approx. 5-7 months post-surgery. In this study, we investigated whether rats exhibited spatial memory deficits at 14 months following BVD and whether these deficits could be exacerbated by administration of cannabinoid (CB) drugs. Twenty-eight adult rats were divided into four groups: (1) sham surgery+vehicle; (2) sham surgery+the CB1/CB(2) receptor agonist WIN55,212-2 ('WIN'); (3) BVD+vehicle; and (4) BVD+WIN. WIN (1.0 or 2.0 mg/kg/day) or vehicle, was administered (s.c.) on days 1-10 and 11-20 (respectively), 30 min before the rats performed in a foraging task. On day 21, the CB receptor inverse agonist, AM251 (3.0 mg/kg, s.c.), was administered before WIN or vehicle. To our surprise, BVD animals were impaired in using the visual cues during the probe test in light. In the dark trials, when visual cues were unavailable, BVD animals were unable to use self-movement cues in homing. However, WIN at 2 mg/kg, significantly improved BVD animals' homing time and number of errors in the dark through strategies other than the improvement in using self-movement cues. Furthermore, AM251 significantly improved heading angle in vehicle-treated animals and the first home choice in WIN-treated animals. These results suggest that at 14 months post-BVD, the animals are not only impaired in path integration, but also piloting and that the spatial memory deficits may be permanent. The involvement of the cannabinoid system is more complicated than expected.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzoxazines; Cannabinoids; Exploratory Behavior; Male; Memory Disorders; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Random Allocation; Rats; Rats, Wistar; Space Perception; Spatial Behavior; Vestibule, Labyrinth

N-methyl-D-aspartate receptors (NMDARs) are mediators of synaptic plasticity and learning and are implicated in the pathophysiology of neuropsychiatric disease and age-related cognitive dysfunction. NMDARs are heteromers, but the relative contribution of specific subunits to NMDAR-mediated learning is not fully understood. We characterized pre-conditioning systemic treatment of the NR2B subunit-selective antagonist Ro 25-6981 for effects on multi-trial, one-trial and low-shock Pavlovian fear conditioning in C57BL/6J mice. Ro 25-6981 was also profiled for effects on novel open field exploration, elevated plus-maze anxiety-like behavior, startle reactivity, prepulse inhibition of startle, and nociception. Three-month (adult) and 12-month old C57BL/6Tac mice were compared for Ro 25-6981 effects on multi-trial fear conditioning, and corticolimbic NR2B protein levels. Ro 25-6981 moderately impaired fear learning in the multi-trial and one-trial (but not low-shock) conditioning paradigms, but did not affect exploratory or anxiety-related behaviors or sensory functions. Memory impairing effects of Ro 25-6981 were absent in 12-month old mice, although NR2B protein levels were not significantly altered. Present data provide further evidence of the memory impairing effects of selective blockade of NR2B-containing NMDARs, and show loss of these effects with ageing. This work could ultimately have implications for elucidating the pathophysiology of learning dysfunction in neuropsychiatric disorders and ageing.

Topics: Acoustic Stimulation; Aging; Animals; Blotting, Western; Cerebral Cortex; Excitatory Amino Acid Antagonists; Exploratory Behavior; Fear; Hot Temperature; Limbic System; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Motor Activity; Pain Measurement; Phenols; Piperidines; Reaction Time; Receptors, N-Methyl-D-Aspartate; Reflex, Startle

Early postnatal maternal deprivation is known to cause long-lasting neurobiological effects. Here, we investigated whether some of the cognitive aspects of these deficits might be related to a disruption of the cholinergic system. Pregnant Wistar rats were individually housed and maintained on a 12:12h light/dark cycle with food and water freely available. The mothers were separated from their pups for 3h per day from postnatal day 1 (PND-1) to PND-10. To do that, the dams were moved to a different cage and the pups maintained in the original home cage, which was transferred to a different room kept at 32 degrees C. After they reached 120-150 days of age, maternal-deprived and non-deprived animals were either sacrificed for brain acetylcholinesterase measurement, or trained and tested in an object recognition task and in a social recognition task as described by Rossato et al. (2007) [Rossato, J.I., Bevilaqua, L. R.M., Myskiw, J.C., Medina, J.H., Izquierdo, I., Cammarota, M. 2007. On the role hippocampal synthesis in the consolidation and reconsolidation of object recognition memory. Learn. Mem. 14, 36-46] and Lévy et al. (2003) [Lévy, F., Melo. A.I., Galef. B.G. Jr., Madden, M., Fleming. A.S. 2003. Complete maternal deprivation affects social, but not spatial, learning in adult rats. Dev. Psychobiol. 43, 177-191], respectively. There was increased acetylcholinesterase activity in hippocampus and perirhinal cortex of the deprived animals. In addition, they showed a clear impairment in memory of the two recognition tasks measured 24h after training. Oral administration of the acetylcholinesterase inhibitors, donepezil or galantamine (1mg/kg) 30min before training reversed the memory impairments caused by maternal deprivation. The findings suggest that maternal deprivation affects memory processing at adulthood through a change in brain cholinergic systems.

Topics: Acetylcholine; Acetylcholinesterase; Aging; Animals; Animals, Newborn; Brain; Disease Models, Animal; Donepezil; Female; Galantamine; Hippocampus; Indans; Learning Disabilities; Male; Maternal Deprivation; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Rats; Rats, Wistar; Social Behavior

We investigated the role of CB1 receptors in hippocampal-dependent memory consolidation mediated by polysialylated neural cell adhesion molecule (PSA-NCAM) during contextual fear conditioning (CFC). The CB1 receptor agonist 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-Delta(8)-tetrahydrocannabinol (HU-210) (0.1 mg/kg) was given immediately after training during the memory consolidation phase, and freezing behavior was measured 24 h after conditioning. Administration of HU-210 attenuated freezing behavior measured in CFC. Western blot analysis showed that CFC induced a decrease in the expression of NCAM-180, but did not change the level of NCAM-140 and increased PSA-NCAM expression measured 24 h after training in the rat hippocampus. HU-210 (0.1 mg/kg) injection did not affect the reduction in NCAM-180 levels induced by CFC, but it blocked the increase in PSA-NCAM expression. Since the dentate gyrus (DG) of the hippocampus is known to be involved in memory consolidation and expresses a high level of PSA-NCAM protein, we measured the effects of CFC and HU-210 administration on PSA-NCAM-immunoreactive (IR) cells in the DG. CFC caused an increase in the number of PSA-NCAM-IR cells in the DG, but not K(i)-67- or doublecortin (DCX)-IR cells. This increase in PSA-NCAM-IR cells was abolished by HU-210 injection. Administration of the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (3 mg/kg immediately before HU-210) inhibited the effects of HU-210 on freezing behavior and PSA-NCAM expression in the DG. These results indicate that activation of CB1 receptors disturbs consolidation of fear memory in CFC, likely by affecting PSA-NCAM expression in the DG, which plays an important role in synaptic rearrangement during the formation of memory traces.

Topics: Animals; Conditioning, Psychological; Dentate Gyrus; Doublecortin Domain Proteins; Doublecortin Protein; Dronabinol; Fear; Freezing Reaction, Cataleptic; Gene Expression; Ki-67 Antigen; Male; Memory Disorders; Microtubule-Associated Proteins; Neural Cell Adhesion Molecule L1; Neuropeptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sialic Acids

Cognitive deficits are commonly associated with maintenance electroconvulsive therapy (ECT). Treatment of these cognitive deficits is important but difficult. Cholinergic pathways are involved in these side effects, and donepezil, a cholinesterase inhibitor, may be useful for improvement of cognition. In this case report, we describe for the first time successful use of donepezil in treating cognitive deficits associated with maintenance ECT. The role of cholinesterase inhibitors in the treatment of cognitive deficits caused by ECT needs further studies.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Electroconvulsive Therapy; Female; Humans; Indans; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Schizophrenia

It is firmly established that the hippocampus, a brain region implicated in spatial learning, episodic memory, and consolidation, contains a high concentration of CB(1) receptors. Moreover, systemic and intrahippocampal administration of cannabinoid agonists have been shown to impair hippocampal-dependent memory tasks. However, the degree to which CB(1) receptors in the hippocampus play a specific functional role in the memory disruptive effects of marijuana or its primary psychoactive constituent Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is unknown. This study was designed to determine whether hippocampal CB(1) receptors play a functional role in the memory disruptive effects of systemically administered cannabinoids, using the radial arm maze, a well characterized rodent model of working memory. Male Sprague-Dawley rats were implanted with bilateral cannulae aimed at the CA1 region of the dorsal hippocampus. The CB(1) receptor antagonist, rimonabant, was delivered into the hippocampus before to a systemic injection of either Delta(9)-THC or the potent cannabinoid analog, CP-55,940. Strikingly, intrahippocampal administration of rimonabant completely attenuated the memory disruptive effects of both cannabinoids in the radial arm maze task, but did not affect other pharmacological properties of cannabinoids, as assessed in the tetrad assay (that is, hypomotility, analgesia, catalepsy, and hypothermia). Infusions of rimonabant just dorsal or ventral to the hippocampus did not prevent Delta(9)-THC-induced memory impairment, indicating that its effects on mnemonic function were regionally selective. These findings provide compelling evidence in support of the view that hippocampal CB(1) receptors play a necessary role in the memory disruptive effects of marijuana.

Topics: Analysis of Variance; Animals; Catheterization; Central Nervous System Agents; Cyclohexanols; Dronabinol; Hippocampus; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Microinjections; Piperidines; Psychotropic Drugs; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant

Hypocholinergic function associated with Alzheimer's disease (AD) is well-accepted hypothesis, in this regard, many research attempts have been made to elevate the reduced cholinergic neurotransmission, among them two main treatment strategies were widely explored, namely stimulation of muscarinic receptor 1 and/or reversible inhibition of acetylcholinesterase (AChE) enzyme. In an attempt to improve the efficacy and to minimize general side effects of these AChE inhibitors, many lead molecules are developed in research; one among them is piperidine derivative. Donazepil is a widely prescribed AChE inhibitor which displays a piperidine ring in its structure. In the present study, we have docked cis-2,6-dimethyl piperidine sulfonamides (3a-i) on AChE enzyme and synthesized by nucleophilic substitution reaction between cis-2,6-dimethyl piperidine and alkyl/aryl sulfonyl chlorides in the presence of triethylamine. These piperidine sulfonamides were subjected to in vitro AChE enzyme inhibition studies and in vivo antiamnesic study to reverse scopolamine induced memory loss in rats. Two derivatives (3a and f) in this class of piperidines (3a-i) showed considerable inhibition against different sources of AChE in vitro and reduced average number of mistakes done by wistar rats as compared to scopolamine treated group in vivo (rodent memory evaluation).

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Catalytic Domain; Cholinesterase Inhibitors; Humans; Male; Memory Disorders; Mice; Models, Molecular; Piperidines; Protein Binding; Rats; Rats, Wistar; Structure-Activity Relationship; Sulfonamides

Deficits in social behaviour is a characteristic of numerous mental disorders including autism, schizophrenia, depression and Alzheimer's disease. For the assessment of pharmacological and genetic experimental disease models, conventional social interaction tasks bear the uncertainty that any drug-induced abnormality of the investigator may feed back to the drug-free companion modifying its reactions. A considerable technical improvement was recently reported by Moy et al. [Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson T, et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behaviours in mice. Genes Brain Behav 2004;3:287-302] in which the drug free partner is confined to a small cage and social contacts of the investigator are recorded uncontaminated of any social reactions of the stranger. Using this novel behavioural paradigm, we here show in C57Bl/6 female mice that sociability (social interaction with a stranger mouse) is not impaired after administration of the anxiolytic diazepam (0.1-1 mg/kg) or the muscarinic antagonist scopolamine hydrobromide (0.1-1 mg/kg). However, social memory tested after a short time interval was impaired by both drugs in a dose-dependent manner (diazepam: > or = 0.5mg/kg; scopolamine: > or = 0.3mg/kg). The scopolamine-induced short-term memory deficit was reversed to normal by the choline esterase inhibitor donepezil (1 mg/kg). Given this dependence of social recognition on the cholinergic system, combined with the clinical observation of reduced social contacts in dementia patients, sociability may offer a novel endpoint biomarker with translational value in experimental models of cognitive dysfunction.

Topics: Animals; Anti-Anxiety Agents; Cholinesterase Inhibitors; Diazepam; Donepezil; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Indans; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Muscarinic Antagonists; Neuropsychological Tests; Nootropic Agents; Piperidines; Random Allocation; Scopolamine; Social Behavior; Time Factors

Place fields of hippocampal pyramidal cells expand asymmetrically when adult rats repeatedly follow the same route. This behaviorally induced expression of neuronal plasticity uses an NMDAR-dependent, LTP-like mechanism and could be used by hippocampal networks to store information. Aged spatial memory-impaired rats exhibit defective experience-dependent place field expansion plasticity. One possible explanation for this aged-associated deficit is alterations in glutamatergic function. In fact, both NMDAR- and AMPAR-mediated field excitatory postsynaptic potentials in CA1 decrease with aging. The current study investigated whether modulation of either AMPA or NDMA receptor activity could restore this experience-dependent plasticity by prolonging AMPAR activity with the ampakine CX516 and modulating the NMDAR with the noncompetitive antagonist memantine. The spatial firing characteristics of multiple CA1 pyramidal cells were monitored under both treatment conditions as aged rats repeatedly traversed a circular track. Compared to the saline baseline condition, acute administration of memantine, but not CX516, reinstated experience-dependent place field expansion. Taken together, these data suggest that pharmacological manipulation of the NMDAR can improve the function of hippocampal networks critical to optimal cognition in aging.

Topics: Age Factors; Aging; Analysis of Variance; Animals; Behavior, Animal; Conditioning, Psychological; Dioxoles; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hippocampus; Male; Memantine; Memory Disorders; Movement; Neuronal Plasticity; Piperidines; Rats; Rats, Inbred F344; Receptors, Glutamate; Space Perception; Theta Rhythm

Hypersexuality in Alzheimer's disease (AD) has been rarely investigated. Hypersexual behaviours should be classified as a sexual obsession and included in the "obsessive-compulsive disorder-like" spectrum. Hypersexuality has no proven treatment, although reports have described reductions of this behaviour using antiandrogen treatment, H2-receptor antagonists and antipsychotic drugs. Serotonin reuptake blockers seem to be effective in the treatment of sexual obsessions or compulsions and less on paraphilic disturbances. We present the case of a 54-year-old male patient with Alzheimer's disease with compulsive sexual behaviour as reported by his wife. A 18-FDG PET scan evidenced prevalent hypometabolism of the right hemisphere, congruent with neuropsychological evaluation. Donepezil, 10 mg per day, produced cognitive improvement but no effects on sexual behaviour. Therapy with SSRI was subsequently started (citalopram): after 60 days, the patient showed improvement in both the compulsive pursuit of sex acts and the level of frustration when refused.

Topics: Alzheimer Disease; Brain; Citalopram; Cognition Disorders; Disease Progression; Donepezil; Fluorodeoxyglucose F18; Humans; Indans; Male; Memory Disorders; Middle Aged; Mood Disorders; Nootropic Agents; Obsessive-Compulsive Disorder; Piperidines; Positron-Emission Tomography; Selective Serotonin Reuptake Inhibitors; Serotonin; Sexual Behavior; Sexual Dysfunctions, Psychological; Treatment Outcome

Cognitive dysfunctions are being recognized as a major roadblock to functional recovery in patients with bipolar disorders. Little is known about the treatment of these cognitive dysfunctions. Donepezil, approved to treat memory dysfunction in Alzheimer's disease, is evaluated for cognitive dysfunctions common in bipolar disorder. Of concern is some evidence that donepezil may trigger affective instability.. All bipolar disordered patients in a private practice setting treated with donepezil for memory problems were analyzed. Patients were assessed for memory improvement and change in psychiatric status with the Clinical Global Impression of Improvement Scale.. Thirty-nine of 58 patients (67%) reported improvement with a mean score of 1.82 (standard deviation+/-0.82). Nine treatments were stopped because of side effects and 4 showed no response. No bipolar I patient received benefits. Thirty-six of 43 (84%) of bipolar II patients showed improvement. Fifty percent of bipolar NOS showed improvement. Four bipolar I patients (57%), 1 bipolar II patient (2%) and 2 bipolar NOS patients (25%) stopped donepezil due to worsening affective symptoms.. This is a naturalistic case series with a single evaluator. Other medications used in treatment were changed as clinically indicated.. This case series suggests utility for donepezil in the treatment of cognitive problems associated with bipolar II disorder and bipolar disorder NOS. Bipolar I patients showed no improvement and a concerning trend to destabilize with donepezil treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bipolar Disorder; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Patient Dropouts; Piperidines; Private Practice; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

It is known that 5-HT(4) receptor agonists increase sAPPalpha levels in the cortex and hippocampus of mice as well as in a model of Alzheimer's disease (AD). As sAPPalpha is thought to have pro-mnesic properties, we assessed whether its increase induces cognitive improvement in a spatial memory task and whether it reverses a scopolamine-induced memory deficit. Mice treated or not treated with scopolamine were trained in the Morris water maze for 3 days. Before the probe test, they received an injection of either a 5-HT(4) receptor agonist (prucalopride or RS 67333), or an acetylcholinesterase inhibitor (donepezil), or both drugs. As expected, scopolamine decreased performance, an effect that was not reversed by the drugs tested when injected alone. However, prucalopride (5 mg kg(-1), s.c.) acted synergistically with donepezil (0.75 mg kg(-1), s.c.) to counteract completely scopolamine-induced amnesia. Western blot analysis of tissue homogenates in the cortex and hippocampus shows that sAPPalpha levels did not differ between saline- and scopolamine-treated mice. Furthermore, a region-dependent drug action was observed since the scopolamine-treated mice display a tendency to increase sAPPalpha levels in the hippocampus after donepezil or in the cortex after prucalopride. Our results suggest that a combined treatment with a 5-HT(4) receptor agonist with an acetylcholinesterase inhibitor has beneficial effects on memory in mice. Moreover, it seems to enhance sAPPalpha levels in two brain regions highly affected in AD. Thus, a drug polytherapy could be interesting not only to enhance cognitive performance and decrease drawbacks but also to get the best action in each brain region.

Topics: Amyloid beta-Protein Precursor; Analysis of Variance; Aniline Compounds; Animals; Benzofurans; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Drug Synergism; Hippocampus; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Motor Activity; Nootropic Agents; Piperidines; Scopolamine; Serotonin 5-HT4 Receptor Agonists; Statistics, Nonparametric

The purpose of the present study was to examine the effect of beta-amyloid (Abeta) oligomers, not the fibrils that make up Abeta plaques, on spatial memory and the cholinergic system in rats. Recently, several researchers have suggested that small assemblies of Abeta, Abeta oligomers, caused memory loss during the early stages of Alzheimer's disease without showing cell death. In the present study, the combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired spatial memory without apoptosis in the CA1 region of the hippocampus. Donepezil, an acetylcholinesterase inhibitor, ameliorated this memory impairment. Therefore we examined acetylcholine (ACh) release from the dorsal hippocampus. A microdialysis study showed that spontaneous release of ACh was not significantly decreased by the combination of Abeta oligomers and cerebral ischemia; however, high K(+)-evoked ACh release was decreased. These results suggest that a combination of Abeta oligomers and cerebral ischemia induces memory impairment by cholinergic synapse dysfunction without apoptosis. This model may be useful for developing new drugs for the treatment of early-phase Alzheimer's disease.

Topics: Acetylcholine; Amyloid beta-Peptides; Animals; Apoptosis; Behavior, Animal; Brain Ischemia; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Down-Regulation; Hippocampus; In Situ Nick-End Labeling; Indans; Male; Maze Learning; Memory Disorders; Microdialysis; Peptide Fragments; Piperidines; Potassium; Rats; Rats, Wistar; Space Perception

The most commonly used model of Down syndrome, the Ts65Dn (TS) mouse, is trisomic for most of the region of MMU16 that is homologous to HSA21. This mouse shares many phenotypic characteristics with people with Down syndrome including behavioral and cognitive alterations. The objective of this study was to analyze the ability of two drugs that improve cognition in different experimental models, the acetylcholinesterase inhibitor donepezil and the non-competitive GABA(A) antagonist pentylenetetrazole (PTZ), to improve the cognitive deficits found in TS mice. The drugs were administered p.o. to TS and CO mice for 8 weeks and a behavioral characterization was performed. Sensorimotor abilities, including vision, hearing, strength and motor coordination, as well as locomotor activity in the home cage, were not modified by any chronic treatment in TS and CO mice. TS mice showed altered equilibrium in the aluminium rod, and this effect was larger under PTZ treatment. This result may indicate a potential adverse effect of PTZ in Ts65Dn mice. Learning and memory were evaluated in TS and CO mice after both treatments in the Morris water maze. Donepezil administration did not modify learning and memory in animals of any genotype. On the other hand, PTZ administration rescued TS performance in the Morris water maze.

Topics: Acetylcholine; Animals; Brain; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Models, Animal; Donepezil; Down Syndrome; Drug Administration Schedule; GABA Antagonists; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Neurologic Mutants; Neural Inhibition; Pentylenetetrazole; Piperidines; Receptors, GABA-A; Treatment Outcome; Trisomy

Oxidative stress is a major factor implicated in the degeneration of cholinergic neurons in Alzheimer's disease. Presently, cholinesterase inhibitors are the mainstay of therapy for Alzheimer's disease. However, the potential of cholinesterase inhibitors as antioxidants, an important aspect for neuroprotection, has not been properly investigated. Therefore, the present study was designed to investigate the influence of antidementia drugs, tacrine and donepezil, on biochemical markers of oxidative stress, glutathione (GSH) and malondialdehyde (MDA), and acetylcholinesterase activity in the brain in a streptozotocin-induced experimental model of dementia in mice. Intracerebral (i.c.) injection of streptozotocin at a dose of 0.5 mg/kg on 1st and 3rd days caused significant deficits in memory function, as evaluated in a passive avoidance test and Morris Water Maze (spatial memory) test 14 days after the 1st dose. Mice were treated with tacrine and donepezil at a dose of 5 mg/kg orally in separate groups. Both tacrine- and donepezil-treated mice showed a significant improvement of the streptozotocin (i.c.)-induced memory impairment. Streptozotocin (i.c.) administration caused a significant decrease in GSH and increase in MDA as compared to control, indicating a state of oxidative stress in the brain of streptozotocin (i.c.) amnesic mice. Treatment of streptozotocin (i.c.) amnesic mice with tacrine or donepezil did not cause significant changes in GSH and MDA levels in the brain as compared to control. Streptozotocin amnesic mice had raised acetylcholinesterase activity in the brain while there was a significant decrease in brain acetylcholinesterase activity in tacrine- and donepezil-treated streptozotocin (i.c.) mice. Thus, results indicate that tacrine and donepezil, beside inhibition of acetylcholinesterase, may also suppress oxidative stress.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Brain; Dementia; Disease Models, Animal; Donepezil; Glutathione; Indans; Male; Malondialdehyde; Maze Learning; Memory Disorders; Mice; Nootropic Agents; Oxidative Stress; Piperidines; Streptozocin; Tacrine

Topics: Aged; Donepezil; Female; Humans; Indans; Jaw; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Tremor

The present study was undertaken to investigate the beneficial effect of HIV protease inhibitor Indinavir on memory deficits associated with experimental dementia of Alzheimer disease's (AD) type. Dementia was induced in Swiss albino mice by administration of Celecoxib (100 mg kg(-1) orally, daily for 9 days) or Streptozotocin (3 mg kg(-1) administered intracerebroventricularly on 1st and 3rd day) and the cognitive behaviors of Swiss albino mice were assessed using Morris water maze test. Brain acetyl cholinesterase (AChE) activity was measured by Ell Mann's method. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively to assess total oxidative stress. Donepezil (0.1 mg kg(-1) i.p.) served as positive control in the present investigation. Celecoxib as well as Streptozotocin (STZ) produced a significant loss of learning and memory. Indinavir (100 and 200 mg kg(-1) orally) successfully attenuated Celecoxib as well as STZ induced cognitive deficits. Higher levels of brain AChE activity, TBARS and lower levels of GSH were observed in Celecoxib as well as STZ treated animals, which were significantly attenuated by Donepezil and Indinavir. Study highlights the potential of Indinavir in memory dysfunctions associated with dementia of AD.

Topics: Acetylcholinesterase; Animals; Antibiotics, Antineoplastic; Brain; Celecoxib; Cyclooxygenase Inhibitors; Dementia; Donepezil; Female; Glutathione; HIV Protease Inhibitors; Indans; Indinavir; Male; Maze Learning; Memory; Memory Disorders; Mice; Nootropic Agents; Oxidative Stress; Piperidines; Pyrazoles; Streptozocin; Sulfonamides; Thiobarbituric Acid Reactive Substances

In this study we evaluated the effect of donepezil on the neurodegeneration and behavioral impairments induced by mild traumatic brain injury (MTBI). Donepezil is an acetylcholinesterase inhibitor that is used to treat Alzheimer's disease. Donepezil was given orally to rats subjected to MTBI. Treatment with a single oral dose of donepezil (12mg/kg) immediately after injury significantly attenuated MTBI-induced neuronal death and cognitive impairment as measured by preservation of neurons in the CA1 region of the hippocampus and a water maze test respectively. However, these neuroprotective effects were prevented by concomitant injection of mecamylamine, a nicotinic acetylcholine-receptor (nAChR) antagonist, indicating that protection is mediated by nAChR activation.

Topics: Animals; Brain; Brain Concussion; Brain Injuries; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Hippocampus; Indans; Male; Maze Learning; Memory Disorders; Nerve Degeneration; Neuroprotective Agents; Nicotinic Agonists; Nicotinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Treatment Outcome

In order to clarify the mechanism of Ginkgo biloba extract (GBE) on learning and memory, we studied the effect of GBE on spatial memory deficits induced by diphenhydramine, pyrilamine and scopolamine using the eight-arm radial maze performance of rats, in comparison with donepezil. Total error (TE), reference memory error (RME) and working memory error (WME) were used as indices of spatial memory deficits. Both GBE and donepezil caused a potent antagonistic effect on the increase in TE, RME and WME induced by diphenhydramine. GBE and donepezil also antagonized scopolamine-induced spatial memory deficits. Although the antagonistic effect of GBE on pyrilamine-induced spatial memory deficits was weak, a significant difference was observed with TE and WME. However, donepezil caused no antagonistic effect on pyrilamine-induced memory deficits. From these findings, we concluded that the effects of GBE are mainly contributable to cholinergic activity and perhaps partly due to a histaminergic mechanism.

Topics: Acetylcholine; Animals; Brain; Brain Chemistry; Diphenhydramine; Donepezil; Ginkgo biloba; Histamine; Histamine H1 Antagonists; Indans; Male; Maze Learning; Memory; Memory Disorders; Muscarinic Antagonists; Neural Pathways; Nootropic Agents; Piperidines; Plant Extracts; Pyrilamine; Rats; Rats, Wistar; Scopolamine; Synaptic Transmission; Treatment Outcome

Recent evidence indicates that the polysialylated neural cell adhesion molecule (PSA-NCAM) is involved in hippocampal plasticity. On the other hand, CB1 receptor activation is known to disturb some hippocampal processes involving plastic changes, such as learning and memory. Therefore, the present study investigated the effect of HU-210, a CB1 receptor agonist, on the expression of PSA-NCAM protein in the dentate gyrus (DG) and CA3 region of the rat hippocampus. It was found that at a dose of 0.1 mg/kg i.p. of HU-210, the number of PSA-NCAM immunoreactive (IR) cells in the DG declined in a time-dependent manner. The decrease in PSA-NCAM expression was observed at 1 and 2 days (ca. 21% and 30%, respectively), but not after 4 h and 4 days following HU-210 administration. However, HU-210 treatment did not change the length density of PSA-NCAM immunopositive processes in CA3 mossy fibers at all the time points measured. The effect observed in the DG on day 2 was blocked by AM-251 (1 mg/kg, i.p.), a CB1 receptor antagonist, given 30 min before HU-210. Neither the number of Ki-67 (IR) cells (a marker of proliferation) nor the number of doublecortin-IR cells (a marker of immature neurons) was affected by HU-210 (0.1 mg/kg, i.p.) treatment at any of the time points. An analysis of co-localization of CB1 receptor protein with PSA-NCAM protein revealed that both proteins were not present in the same population of neurons in the subgranular layer of the DG. The observed changes in PSA-NCAM expression were not related to the reduction of proliferation or differentiation of newly born cells, but were possible due to alternations in the synaptic activity in the DG. However, such alteration in the PSA-NCAM expression may change the timing of the functional maturation of newly born neurons. Moreover, the above finding suggests that acute activation of CB1 receptors may result in the stiffening of the hippocampal structure and susceptibility to plastic changes and may lead to functional impairment governed by alterations in the hippocampal structure.

Topics: Animals; Cannabinoids; Cell Count; Cell Differentiation; Cell Proliferation; Dentate Gyrus; Dose-Response Relationship, Drug; Doublecortin Domain Proteins; Doublecortin Protein; Down-Regulation; Dronabinol; Excitatory Amino Acid Antagonists; Immunohistochemistry; Ki-67 Antigen; Male; Memory Disorders; Microtubule-Associated Proteins; Neural Cell Adhesion Molecule L1; Neuronal Plasticity; Neurons; Neuropeptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sialic Acids; Stem Cells; Time Factors

Previous work implied that the hippocampal cannabinoid system was particularly important in some forms of learning, but direct evidence for this hypothesis is scarce. We therefore assessed the effects of the synthetic cannabinoid HU210 on memory and hippocampal activity.. HU210 (100 microg kg(-1)) was administered intraperitoneally to rats under three experimental conditions. One group of animals were pre-trained in spatial working memory using a delayed-matching-to-position task and effects of HU210 were assessed in a within-subject design. In another, rats were injected before acquisition learning of a spatial reference memory task with constant platform location. Finally, a separate group of animals was implanted with electrode bundles in CA1 and CA3 and single unit responses were isolated, before and after HU210 treatment.. HU210 treatment had no effect on working or short-term memory. Relative to its control Tween 80, deficits in acquisition of a reference memory version of the water maze were obtained, along with drug-related effects on anxiety, motor activity and spatial learning. Deficits were not reversed by the CB(1) receptor antagonists SR141716A (3 mg kg(-1)) or AM281 (1.5 mg kg(-1)). Single unit recordings from principal neurons in hippocampal CA3 and CA1 confirmed HU210-induced attenuation of the overall firing activity lowering both the number of complex spikes fired and the occurrence of bursts.. These data provide the first direct evidence that the underlying mechanism for the spatial memory deficits induced by HU210 in rats is the accompanying abnormality in hippocampal cell firing.

Topics: Animals; Behavior, Animal; Cannabinoids; Dronabinol; Electrophysiology; Hippocampus; Male; Maze Learning; Memory; Memory Disorders; Morpholines; Motor Activity; Neurons; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Space Perception

To characterize deficits in nonverbal recognition memory and functional brain changes associated with these deficits in Alzheimer disease (AD).. Using O-15 PET, we studied 11 patients with AD and 17 cognitively intact elders during the combined encoding and retrieval periods of a nonverbal recognition task. Both task conditions involved recognition of line drawings of abstract shapes. In both conditions, subjects were first presented a list of shapes as study items, and then a list as test items, containing items from the study list and foils. In the titrated demand condition, the shape study list size (SLS) was adjusted prior to imaging so that each subject performed at approximately 75% recognition accuracy; difficulty during PET scanning in this condition was approximately matched across subjects. A control task was used in which SLS = 1 shape.. During performance of the titrated demand condition, SLS averaged 4.55 (+/-1.86) shapes for patients with AD and 7.53 (+/-4.81) for healthy elderly subjects (p = 0.031). However, both groups of subjects were closely matched on performance in the titrated demand condition during PET scanning with 72.17% (+/-7.98%) correct for patients with AD and 72.25% (+/-7.03%) for elders (p = 0.979). PET results demonstrated that patients with AD showed greater mean differences between the titrated demand condition and control in areas including the left fusiform and inferior frontal regions (Brodmann areas 19 and 45).. Relative fusiform and inferior frontal differences may reflect the Alzheimer disease (AD) patients' compensatory engagement of alternate brain regions. The strategy used by patients with AD is likely to be a general mechanism of compensation, rather than task-specific.

Topics: Adaptation, Physiological; Aged; Alzheimer Disease; Brain Mapping; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Female; Frontal Lobe; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Nootropic Agents; Oxygen Radioisotopes; Pattern Recognition, Visual; Phenylcarbamates; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Rivastigmine; Temporal Lobe

We investigated the participation of gamma-aminobutyric acid (GABA) neurons of the medial septal area in eight-arm radial maze performance in rats. The intra-septal injection of muscimol, a GABA(A) agonist, caused an increase in total error and working memory error. On the other hand, no significant effect was observed with reference memory error. Donepezil and tacrine (cholinesterase inhibitors) antagonized the muscimol-induced spatial memory deficits. Histidine (1500 mg/kg, i.p.) also improved the total error and working memory error induced by muscimol. At this dose, histidine caused a significant increase in the histamine content of the cortex, hippocampus, and hypothalamus in rats. In addition, the intra-hippocampal injection of histamine also antagonized muscimol-induced spatial memory deficits. The practical conclusion is that the GABA(A) receptor of the medial septal area plays an important role in working memory, and also, the disturbance of working memory induced by muscimol is mediated not only by cholinergic but also by histaminergic systems in the spatial memory of rats.

Topics: Animals; Brain Chemistry; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; GABA Agonists; GABA-A Receptor Agonists; Histamine; Histidine; Indans; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Microinjections; Muscimol; Piperidines; Rats; Tacrine

We investigated the role of hippocampal group I metabotropic glutamate receptors (mGlu(1) receptors) in the retrieval process of spatial memory using 8-arm radial maze performance with 4 arms baited. In addition, the participation of the cholinergic system in memory deficits induced by mGlu(1) receptors antagonist was studied. Intrahippocampal injection of (R,S)-1-Aminoindan-1,5-dicarboxylic acid (AIDA), a mGlu(1) receptor antagonist, significantly increased total error, reference memory error and working memory error at a dose of 20 nmol/side. Donepezil (0.5 and 1.0 mg/kg, p.o.) showed an ameliorative effect on AIDA-induced memory deficits. Improvement by donepezil of AIDA-induced memory deficits was antagonized by scopolamine (5 nmol/side) but not by mecamylamine (200 nmol/side) at a dose that did not affect performance. These findings clearly indicate that hippocampal mGlu(1) receptors play an important role in the retrieval of spatial memory. Furthermore, we found that hippocampal mGlu(1) receptors were closely associated with muscarinic receptors in memory performance.

Topics: Animals; Cholinergic Agents; Cholinergic Antagonists; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hippocampus; Indans; Male; Maze Learning; Mecamylamine; Memory Disorders; Piperidines; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Scopolamine

We report here that local hippocampal WIN-55,212-2 implants release this cannabinoid agonist for extended periods, the release is restricted to the implanted brain region and is behaviorally active. Radiolabeled WIN-55,212-2 was implanted bilaterally into the CA3 region of the dorsal hippocampus by means of fused silica capillaries. Significant amounts of the compound were released from the implants for at least 10 days. No labeled WIN-55,212-2 was detected in other brain regions, for example, the cortex, amygdala, thalamus, hypothalamus, and pons. In a separate experiment, radiolabeled WIN-55,212-2 was implanted chronically into the same hippocampal region, and rats were assessed 8 days later in the object-recognition test. In contrast to controls, rats implanted with WIN-55,212-2 were unable to differentiate familiar and unfamiliar objects. Object recognition was reinstated by the cannabinoid antagonist SR141716A, as rats implanted with both WIN-55,212-2 and SR141716A did not differ from controls. Thus, chronic hippocampal WIN-55,212-2 implants impaired recognition memory via the CB1 receptor. The memory-impairing effects of acute cannabinoid treatments are well known, but the effects of chronic treatments are controversial. The rate and magnitude of tolerance, however, have been shown to be brain-area specific and cell-type specific. Here we show that chronic hippocampal treatments impair memory, suggesting that no tolerance develops in the hippocampus towards the memory-impairing effects of cannabinoids. The data also suggest that chronic, brain-area-specific effects of cannabinoids can be studied by the novel method described here.

Topics: Animals; Benzoxazines; Cannabinoids; Conditioning, Operant; Delayed-Action Preparations; Discrimination Learning; Drug Administration Schedule; Drug Implants; Drug Tolerance; Hippocampus; Male; Memory Disorders; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Recognition, Psychology; Rimonabant; Tissue Distribution

Childhood epilepsy is one of the main risk factors for a variety of problems involving cognition and behavior. Pentylenetetrazol (PTZ) kindling is currently an acceptable model for epilepsy research. The objectives of this study are to clarify the learning and mnemonic characteristics of PTZ kindling in developing mice, and to examine the effects of thioperamide and JNJ-5207852, two histamine H(3) receptor antagonists and donepezil, an acetylcholinesterase (AChE) inhibitor, on learning and memory deficits induced by PTZ kindling in the brains of developing mice. PTZ kindling led to learning and mnemonic deficits as assessed by social discrimination, acoustic fear conditioning, water maze and passive avoidance tests. Thioperamide and JNJ-5207852, ameliorated PTZ kindling-induced learning and mnemonic deficits in all tests except for the water maze test. In addition, the learning and mnemonic impairments induced by PTZ kindling were significantly improved by donepezil in all tests. These findings suggest that histamine and acetylcholine are involved in the different processes of learning and memory in the brain and that histamine H(3) receptor antagonists might be useful in the treatment of cognitive impairment in epilepsy.

Topics: Animals; Avoidance Learning; Convulsants; Donepezil; Electric Stimulation; Female; Histamine Antagonists; Indans; Kindling, Neurologic; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Nootropic Agents; Pentylenetetrazole; Piperidines; Recognition, Psychology

We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD.

Topics: ADAM Proteins; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antibodies, Monoclonal; Basigin; Behavior, Animal; Blotting, Western; Brain; Cell Count; Cytoskeletal Proteins; Dicyclomine; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Escape Reaction; Gene Expression; GTP-Binding Proteins; Humans; Immunohistochemistry; Memory Disorders; Mice; Mice, Transgenic; Muscarinic Antagonists; Nuclear Proteins; Piperidines; Protein Kinase C; Reaction Time; Receptor, Muscarinic M1; Spatial Behavior; Spiro Compounds; tau Proteins; Thiazoles; Time Factors

The cholinergic system undergoes changes with aging and in Alzheimer's disease. The effects of the anticholinesterase drugs galantamine and donepezil were studied in a model with sodium nitrite-induced hypoxia in rats. The animals were trained in the shuttle-box active avoidance test and in step-through and step-down passive avoidance tests. In the active avoidance test, hypoxic rats showed a decrease in the number of avoidances in the learning session and in retention. The hypoxic rats receiving galantamine showed an increase in the number of avoidances during the learning session. The groups in hypoxia treated with donepezil had an increased number of avoidances in the learning session. In memory retention tests, significant differences were not observed in the hypoxic animals treated with galantamine or donepezil. In the step-through passive avoidance test, rats treated with galantamine had no change in the latency of reactions during the learning session and memory retention tests. In the step-down passive avoidance test, the animals treated with galantamine had increase latency of reactions during the learning and short- or long-memory retention tests. The hypoxic rats receiving donepezil had increased latency of reactions in the step-down short memory retention test. Our results suggest that galantamine and donepezil improve cognitive functions in a model of hypoxia.

Topics: Animals; Avoidance Learning; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Galantamine; Hypoxia, Brain; Indans; Male; Memory; Memory Disorders; Piperidines; Rats; Rats, Wistar; Sodium Nitrite; Time Factors

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Humans; Indans; Memory Disorders; Nootropic Agents; Piperidines; Treatment Failure

Topics: Cholinesterase Inhibitors; Donepezil; Humans; Indans; Memory Disorders; Multiple Sclerosis; Piperidines; Randomized Controlled Trials as Topic

Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer's disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of beta-amyloid (Abeta) and behavioral deficits during adulthood are useful for investigating this question.. The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Abeta plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9-10 months of age, Tg2576-transgenic [Tg(+)] mice develop Abeta plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(-)] mice.. Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Abeta plaque number was quantified.. Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Abeta plaques.. These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Abeta plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Cholinesterase Inhibitors; Conditioning, Psychological; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Fear; Genetics, Behavioral; Heterozygote; Humans; Indans; Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Physostigmine; Piperidines; Plaque, Amyloid; Spatial Behavior

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. ICV STZ is known to impair cholinergic neurotransmission by decreasing choline acetyltransferase (ChAT) levels, glucose and energy metabolism in brain and synthesis of acetyl CoA. However, no reports are available regarding the cholinesterase inhibitors in this model. In aging brain, reduced energy metabolism increases glutamate release, which is blocked by L-type calcium channel blockers. These calcium channel blockers have shown beneficial effects on learning and memory in various models of cognitive impairment. The present study was designed to investigate the influence of chronic administration of donepezil (cholinesterase inhibitor, 1 and 3 mg/kg) and lercanidipine (L-type calcium channel blocker, 0.3 and 1 mg/kg) on cognitive impairment in male Sprague-Dawley rats injected twice with ICV STZ (3 mg/kg) bilaterally on days 1 and 3. ICV STZ injected rats developed a severe deficit in learning and memory indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to control rats. Cholinesterase activity in brain was significantly increased in ICV STZ injected rats. Donepezil dose-dependently inhibited cholinesterase activity and improved performance in memory tests at both the doses. Lercanidipine (0.3 mg/kg) showed significant improvement in memory. When administered together, the effect of combination of these two drugs on memory and cholinesterase activity was higher than that obtained with either of the drugs when used alone.

Topics: Animals; Avoidance Learning; Brain; Calcium Channel Blockers; Cerebral Ventricles; Choline O-Acetyltransferase; Cholinesterase Inhibitors; Dihydropyridines; Donepezil; Drug Combinations; Indans; Injections; Male; Maze Learning; Memory; Memory Disorders; Piperidines; Rats; Rats, Sprague-Dawley; Streptozocin

Delta9-THC and synthetic cannabinoids produce memory impairment in humans as well as in laboratory animals. The high concentration of cannabinoid CB1 receptors and the presence of endocannabinoids in the hippocampus suggest that a cannabinoid neurochemical system may play a role in learning and memory processes. Thus, the objective of the present work was to study the effect of the cannabinoid antagonist SR141716A (SR) on memory acquisition, consolidation and retrieval in a recently developed elevated T-maze (ETM) model of anxiety and memory. In addition, we investigated whether pre-training SR administration was capable of reversing scopolamine-induced memory impairment. Adult male mice were exposed to the closed arm as many times as necessary for the animals to reach the avoidance criterion of remaining in the closed arm for 300 s; they were then tested (exposed to the closed arm) 24 h and 7 days after the training. SR (0.5, 1.0 or 2.0 mg/kg) was administered i.p. 20 min before the training, immediately after training or 20 min before the test in the mice. The elevated plus-maze (EPM) was used to investigate a possible influence of SR on locomotion and on the anxiety-related behavior. SR provoked memory improvement, which was observed when the drug was administered before (effect on memory acquisition/consolidation) or immediately after the training (effect on memory consolidation), but not when the drug was administered before the test (effect on memory retrieval). Also, SR administration reversed scopolamine-induced amnesia. These effects were observed in the absence of changes in locomotion or anxiety levels. Our results demonstrate that the blockade of cannabinoid receptors may improve memory acquisition and consolidation in the ETM model.

Topics: Animals; Anxiety; Cannabinoid Receptor Modulators; Drug Interactions; Hippocampus; Male; Maze Learning; Memory; Memory Disorders; Mice; Motor Activity; Muscarinic Antagonists; Neural Pathways; Neurons; Nootropic Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Scopolamine

We investigated the effects of memantine and donepezil on amyloid beta (Abeta)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Abeta1-40 was microinjected bilaterally (1 nmol/side) into both CA1 and CA3 subfields of the hippocampus in rats that had previously performed the DMTP task. Memantine (20 mg/(kg day), s.c.) was continuously infused by an osmotic minipump for 4 weeks from 3 days before the microinjection of Abeta. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Abeta1-40 into the hippocampus resulted in a delayed, but persistent impairment of DMTP performance, which appeared more than 50 days after the injection. Memantine prevented the development of Abeta-induced memory impairment, while donepezil symptomatically alleviated the deficits. Because of a ceiling effect, the combination of donepezil with memantine failed to produce any additive or synergic effects. These results support the clinical data showing that memantine and donepezil are effective for the treatment of Alzheimer's disease. Moreover, it is suggested that memantine is effective for preventing Abeta-induced short-term memory impairment.

Topics: Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Conditioning, Operant; Donepezil; Drug Administration Routes; Drug Interactions; Excitatory Amino Acid Antagonists; Food Deprivation; Hippocampus; Indans; Male; Memantine; Memory Disorders; Peptide Fragments; Piperidines; Rats; Rats, Inbred F344; Reaction Time; Time Factors

Topics: Artifacts; Cholinergic Antagonists; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Humans; Indans; Memory Disorders; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Reproducibility of Results; Research Design; Treatment Outcome; Urinary Bladder, Neurogenic

Selegiline, a monoamine oxidase-B inhibitor, is reported to improve memory and learning in dementia of Alzheimer's type. However, only a few studies have reported its use in animal models. Here, we evaluated the effects of selegiline only or its combined use with donepezil, a selective acetylcholinesterase inhibitor on memory impairment, using a Morris water maze. Selegiline dose-dependently attenuated ethylcholine aziridinium ion-induced memory impairment. Co-administration of selegiline and donepezil, at doses that do not exert efficacy individually, significantly ameliorated scopolamine+p-chlorophenylalanine-induced memory deficits. These results suggest that selegiline improves memory impairment mediated by the cholinergic system, and provide evidence of the usefulness of co-treatment with selegiline and donepezil for treating spatial deficits in dementia.

Topics: Analysis of Variance; Animals; Antiparkinson Agents; Aziridines; Behavior, Animal; Choline; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Synergism; Escape Reaction; Fenclonine; Indans; Male; Maze Learning; Memory Disorders; Piperidines; Rats; Rats, Inbred F344; Reaction Time; Scopolamine; Selegiline; Time Factors

In this study, we examined the performance of vasopressin V1a receptor (V1aR) and vasopressin V1b receptor (V1bR) knockout (KO) mice compared to wild-type (WT) mice in an eight-arm radial maze. V1aR KO mice exhibited an impairment of spatial memory in comparison to WT mice. By contrast, we did not observe any significant differences between the V1bR KO mice and the WT mice in the eight-arm radial maze. Moreover, OPC-21268, a selective V1aR antagonist, impaired spatial memory in the eight-arm radial maze in WT mice characterized by an increased number of errors. These results suggest that the V1aR controls spatial memory in mice.

Topics: Analysis of Variance; Animals; Antidiuretic Hormone Receptor Antagonists; Choice Behavior; Dose-Response Relationship, Drug; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Quinolones; Receptors, Vasopressin; Spatial Behavior

A significant impairment of learning and memory-related behavior was induced in mice on the 7th and 14th days after olfactory bulbectomy (OBX), as measured by a passive avoidance task. The involvement of the N-methyl-D-aspartate (NMDA) receptor ion-channel complex for learning and memory-related behavior impairment was examined by the intracerebroventricular administration of several NMDA receptor-related agonists and in combination with antagonists. The NMDA receptor agonist NMDA (1 ng/mouse) and the polyamine site agonist spermidine (1 micro g/mouse) improved learning and memory-related behavior impairment. In contrast, the glycine agonist D-cycloserine (0.2, 1 and 5 micro g/mouse) had no effect on learning and memory-related behavior impairment. The improved effects by NMDA and spermidine were reversed by the coadministration of D-APV, a competitive NMDA receptor antagonist, MK-801, an NMDA ion-channel blocker and ifenprodil, a polyamine site antagonist, respectively. These results suggest that the degeneration of NMDA receptors and polyamine sites in the NMDA receptor ion-channel complex may be involved in the OBX-induced impairment of learning and memory-related behavior.

Topics: 2-Amino-5-phosphonovalerate; Animals; Avoidance Learning; Cycloserine; Disease Models, Animal; Dizocilpine Maleate; Drug Therapy, Combination; Injections, Intraventricular; Male; Memory Disorders; Mice; N-Methylaspartate; Olfactory Bulb; Piperidines; Receptors, N-Methyl-D-Aspartate; Spermidine; Time Factors

This study was performed to investigate whether or not the histamine H3-antagonist clobenpropit can ameliorate spatial memory deficits induced by MK-801 (0.3 microg per site) as evaluated by an eight-arm radial maze task of rats. A bilateral intrahippocampal (i.h.) injection of clobenpropit (5, 10 microg per site, dose-dependent) markedly improved the working and reference memory deficits induced by MK-801. Its ameliorating effect was potentiated by histidine, but completely antagonized by immepip (2.5 microg per site), a selective H3-agonist. alpha-Fluoromethylhistidine (FMH, 25 microg per site), a selective histidine decarboxylase inhibitor prevented the ameliorating effect of clobenpropit on the working memory deficits induced by MK-801. In addition, the H(1-antagonist pyrilamine, but not the H2-antagonist cimetidine, also inhibited the procognitive effects of clobenpropit. Both FMH and pyrilamine did not significantly modulate the effect of clobenpropit on reference memory. Therefore, the results of this study suggest that the procognitive effects of clobenpropit in MK-801-induced working memory deficits is mediated by increasing endogenous histamine release. In addition, the ameliorating effect of clobenpropit on reference memory might be due to the increased release of neurotransmitters other than histamine.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Histamine Antagonists; Imidazoles; Male; Maze Learning; Memory Disorders; Piperidines; Rats; Rats, Sprague-Dawley; Spatial Behavior; Thiourea

Donepezil (Aricept), a long-acting cholinesterase inhibitor, is widely used in the treatment of Alzheimer's disease to improve cognition and memory. Many drugs within the class of cognition-enhancing agents, both currently approved medications and those under development, have clinical indications narrowly relegated to Alzheimer's disease. The purpose of this study was to determine whether the efficacy attributed to donepezil in its ability to improve delayed matching accuracy by monkeys was independent of age. Male and female rhesus monkeys (n = 17) ranging from 9to 29 yr of age were administered donepezil (10, 25, 50, and 100 microg/kg, im) during 4 discrete test days. Donepezil treatment improved average task accuracy, but intersubject variability prohibited statistical significance. When animals were considered individually, the most effective dose of donepezil was associated with a highly significant increase in group task performance that was consistent with enhanced recall during testing. The variability associated with the dose-response analysis was attributable primarily to subject age, such that older monkeys required higher doses of donepezil. Yet at doses that were effective in all subjects, there was no relationship between age and the improvement in task accuracy. Likewise, there was no association between baseline task proficiency and improvement in task accuracy.

Topics: Age Factors; Aging; Animals; Cognition; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Female; Indans; Macaca mulatta; Male; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Recovery of Function; Sex Factors; Treatment Outcome

The present study was conducted to determine the effects of two potent 5-HT4 receptor agonists, BIMU 1 (1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo (3.2.1)-oct-3-yl]-2-oxo-1H) benzimidazole-1-carboxamide hydrochloride; 1, 3, 10 mg/kg, i.p.) and RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone; 0.25, 0.5, 1 mg/kg, i.p.) on the learning impairment induced by the muscarinic acetylcholine receptor antagonist, scopolamine (1 mg/kg) in mice. Working memory was examined by observing spontaneous alternation behavior in the Y-maze test. Both BIMU 1 (10 mg/kg) and RS 67333 (1 mg/kg) prevented the scopolamine-induced alternation deficits, whereas no effect could be evidenced on locomotor or emotional indices. The reversal actions of BIMU 1 and RS 67333 on this cognitive dysfunction were abolished by the selective 5-HT4 receptor antagonist GR 125487 (1-[2-[(methyl sulfonyl)-amino]-ethyl]-4-piperidinyl-methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate; 10 mg/kg, i.p.). When given alone at the same doses, none of the three serotonergic agents had any measurable effect. These results demonstrate the ability of 5-HT4 receptor agonists to reverse spontaneous working memory deficits and further confirm the therapeutic potential of such ligands in the treatment of cognitive alterations that associate short-term working memory disorders and cholinergic hypofunction.

Topics: Aniline Compounds; Animals; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Locomotion; Male; Memory; Memory Disorders; Mice; Piperidines; Receptors, Serotonin, 5-HT4; Scopolamine; Serotonin 5-HT4 Receptor Agonists

To investigate the effectiveness of donepezil hydrochloride (Aricept) in treating persistent memory deficits in people with traumatic brain injury.. Single subject ABAC design was used so that each participant could serve as their own control.. Seven TBI survivors with persistent memory dysfunction, at least 1.5 years post-injury, underwent two 6-month trials of Aricept. The following tests were used to assess memory and cognition: Brief Visual Memory Test-Revised (BVMT-R), Hopkins Verbal Learning Test, Digit Span and Letter Number Sequence sub-test of the Wechsler Adult Intelligence Scale-III, Controlled Oral Word Association Test and Memory Functioning Questionnaire.. During the first treatment phase, participants received 5 mg/day of Aricept for 1 month, increasing to 10 mg/day of Aricept for an additional 5 months. During the second treatment phase, participants received 5 mg/day of Aricept for the entire 6 months.. A repeated measures analysis of variance indicated significant improvement on immediate and delayed memory portions of the BVMT-R when taking 10 mg/day of Aricept.. Findings contribute to the growing body of research into the use of Aricept in treating memory deficits in TBI survivors and support the need for further research.

Topics: Adult; Analysis of Variance; Brain Injuries; Cholinesterase Inhibitors; Chronic Disease; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Pilot Projects; Piperidines; Psychiatric Status Rating Scales

The effects of chronic exposure to cannabinoids on short-term memory in rats were assessed during repeated daily injections of an initially debilitating dose (3.75 mg/kg) of the potent CB1 cannabinoid receptor ligand, WIN 55,212-2. Delayed nonmatch to sample (DNMS) performance was assessed over a 35-day exposure period in which performance was initially disrupted during the first 21 days of exposure but recovered by day 30 and was stable at pre-drug levels for 5 days thereafter. Withdrawal was precipitated by injections of the CB1 receptor antagonist SR141716A and transiently reduced performance for 2 days but was restabilized to pre-drug levels within 3-4 days. Concomitant recording from identified CA1 and CA3 hippocampal neurons demonstrated a marked correspondence in the time course of suppression of peak firing in the sample and delay phases of the task to the drug-induced performance deficits over the same days of exposure. Hippocampal encoding of task-relevant events and performance levels "tracked" each other on a daily basis throughout the chronic cannabinoid treatment and withdrawal regimen. However, hippocampal neuronal activity in the nonmatch phase of the task was unaffected by the chronic cannabinoid treatment or withdrawal, suggesting that only a select population of hippocampal neurons and synapses are involved in cannabinoid-sensitive short-term memory processes.

Topics: Action Potentials; Adaptation, Physiological; Animals; Benzoxazines; Cannabinoids; Drug Administration Schedule; Drug Tolerance; Hippocampus; Male; Marijuana Abuse; Memory Disorders; Morpholines; Naphthalenes; Neurons; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Reaction Time; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome; Synaptic Transmission

The objective of the current study was to explore the potential cognitive benefits of an anticholinesterase inhibitor, donepezil, in a former chronic drug user. A neuropsychological test battery composed of the vocabulary and matrix reasoning subtests of the Wechsler adult intelligence scale-III, measures of everyday executive functioning (behavioural assessment of the dysexecutive syndrome [BADS]), and verbal learning and memory tasks (California verbal learning test-II; Rivermead behavioural memory test) was completed at baseline, at 3 months after introducing donepezil, and at 3 months after donepezil was discontinued. After donepezil treatment, substantial improvements were found on tasks of nonverbal fluid reasoning (i.e. matrix reasoning) and other executive functioning tests (i.e. BADS). At entry into the study, poor academic performance and subjective problems with memory and concentration were reported, particularly after amphetamine use (i.e. MDMA and crystal methamphetamine); after donepezil treatment, dramatic increases in memory, concentration and academic achievement were observed. The finding of improvements in tests of executive functioning and in academic performance in this case study, together with the minimal adverse side effects of donepezil, warrants the investigation of controlled studies of cholinergic enhancement in chronic amphetamine and other drug users.

Topics: Adult; Amphetamine-Related Disorders; Attention; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Male; Memory Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Neuropsychological Tests; Piperidines

FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate] is a novel antidementia drug which has been demonstrated to have potential cognitive-improving actions through enhancement of somatostatin release. Since the mechanism of action is different from cholinesterase inhibitors (CEIs), FK960 might be more efficacious at alleviating cognitive deficiencies than CEIs alone, particularly when used in combination therapies with CEIs. We examined the ability of FK960 and donepezil, a CEI, to improve memory deficits in three rat models of dementia: scopolamine-treated rats, rats received with bilateral nucleus basalis magnocellularis (NBM) lesions, and aged rats using the passive avoidance task. FK960 (0.1-10 mg/kg ip) significantly ameliorated the memory deficits in all three models. Donepezil (0.032-3.2 mg/kg ip) significantly improved the deficits induced by both scopolamine or by NBM lesion, but no significant effect was observed in the aged rat model. To determine whether concomitant treatment would be more effective, we coadministered FK960 and donepezil in NBM-lesioned rats using the same task. Concurrent administration of FK960 and donepezil at dosages that were suboptimal when the compounds were administered alone (FK960, 0.1 mg/kg; donepezil, 0.1 mg/kg) significantly improved memory impairment in the animals. Furthermore, coadministration of FK960 and donepezil at optimal dosages for both (FK960, 1 mg/kg; donepezil, 0.32 mg/kg) produced marked amelioration of memory deficits that was more efficacious than when either compound was administered individually. These results demonstrate that FK960 is more efficacious than CEIs in improving memory deficits, and that FK960 has synergistic efficacy when combined with CEIs.

Topics: Aging; Animals; Avoidance Learning; Basal Nucleus of Meynert; Benzamides; Donepezil; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Indans; Male; Memory Disorders; Nootropic Agents; Piperazines; Piperidines; Rats; Rats, Wistar; Scopolamine

This study reports a series of spatial discrimination procedures in a Morris-type maze to investigate the effects of delta9-tetrahydrocannabinol (delta9-THC) on different phases of learning and memory in mice. Adult male mice were given training trails to find the submerged platform at a fixed location in the water maze adapted for mice. In additional experiments, mice were trained with the repeated acquisition procedure to test the working memory. Results indicate that delta9-THC (8 mg/kg i.p.) 30 min pretest impaired specifically the acquisition of spatial learning and the performance of mice in the working memory task, while consolidation and retrieval of a previously learned task were not affected. There was no evidence of motoric difficulty, as the number of quadrant line crossings was not decreased and no visible sign of sensorimotor disturbance was observed during swimming. Pretreatment with SR 141716A (1 mg/kg i.p.), a CB1 cannabinoid receptor antagonist, significantly prevented the learning deficits in the water maze. These findings show that delta9-THC impairs spatial discrimination learning in a selective way in the water maze in mice and that these deficits may be mediated by cannabinoid receptors.

Topics: Animals; Dose-Response Relationship, Drug; Dronabinol; Male; Maze Learning; Memory Disorders; Mice; Piperidines; Psychotropic Drugs; Pyrazoles; Reaction Time; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spatial Behavior

To evaluate effect of TAK-147 on spatial memory deficit induced by scopolamine.. Morris water maze was used to measure spatial memory in rats and open field test was used to analyse locomotor activity.. In the acquisition memory process, scopolamine (0.4 mg/kg, ip) markedly increased the escape latency to the platform. Ip injection of both TAK-147 and donepezil ameliorated scopolamine-induced deficit, dose-related and significant effect was obtained at doses of 0.1-1.0 mg/kg. In the memory retrieval process, increased latency induced by scopolamine (1.5 mg/kg, ip) was also significantly reversed by treatment with TAK-147 (0.1, 0.3, and 1.0 mg/kg), donepezil (0.3 and 1.0 mg/kg), and tacrine (3 and 5 mg/kg), respectively. TAK-147 has a little potent efficacy to donepezil, and was more potent than tacrine. In the locomotor test, both TAK-147 and donepizil created no appreciable change of locomotor activities, compared with scopolamine or saline.. TAK-147 plays an important role in spatial cognition, and this result provides additional evidence that TAK-147 is an ideal AChE inhibitor and is useful for the treatment of Alzheimer's disease.

Topics: Animals; Benzazepines; Cholinesterase Inhibitors; Donepezil; Indans; Male; Maze Learning; Memory Disorders; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Scopolamine; Tacrine

The purpose of these studies were threefold. Firstly, to further characterize the effect of perforant path transection on a test of short-term memory: delayed matching (or nonmatching)-to-position [D(N)MTP]. Secondly, to evaluate the effect of a transient cerebral ischaemia in the same task. Both surgical procedures were chosen as they produce a CNS lesion similar to that described in Alzheimer's Disease (AD). Thirdly, the effect of the acetylcholinesterase inhibitor, donepezil (Aricept(R), E2020), on the resulting cognitive impairment was studied. Perforant path transection produced a robust, delay-dependent impairment of choice accuracy in rats performing either a delayed matching- or nonmatching-to-position task. Sample latency was also reduced following lesion, yet the lesion-induced impairment was not affected by increasing the response requirement at the sample stage. An 11-min period of transient ischaemia (two-vessel occlusion model) resulted in almost complete loss of hippocampal CA1 pyramidal cells and a delay-dependent impairment in DMTP performance. However, unlike perforant path lesions, this deficit was unstable and declined in magnitude over the experimental period. Increasing the delay interval restored this deficit. Donepezil, at doses that robustly attenuated a scopolamine (0.06 mg/kg s.c.)-induced DMTP accuracy impairment in naïve, unoperated rats, had no effect against either lesion-induced impairment. The results are considered in terms of the effectiveness of acetylcholinesterase inhibitors in noncholinergic-based preclinical cognitive models.

Topics: Alzheimer Disease; Animals; Brain Infarction; Brain Ischemia; Cell Death; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Hippocampus; Indans; Male; Memory Disorders; Muscarinic Antagonists; Perforant Pathway; Piperidines; Rats; Rats, Wistar; Reaction Time; Reperfusion Injury; Scopolamine

We investigated the characteristics of delta9-tetrahydrocannabinol (THC)-induced impairment of learning and memory using an 8-arm radial maze task, a water maze, a visual discrimination task with 2 figures and a passive avoidance test in rats. THC (6 mg/kg, i.p.) impaired spatial memory in the standard task of the 8-arm radial maze. THC (4-6 mg/kg, i.p.) selectively impaired working memory in a reference and working memory task of the 8-arm radial maze. Even at a dose of 10 mg/kg, THC did not impair spatial memory in the water maze. In addition, THC at a dose of 6 mg/kg, which had inhibitory effects in the 8-arm radial maze, did not affect performance in the visual discrimination task. These results indicate that at low doses (2-6 mg/kg), THC may not produce visual function abnormalities. THC impaired retrieval (6 mg/kg, i.p.) as well as acquisition (10 mg/kg, i.p.) in the passive avoidance test. The consolidation process was also impaired by i.c.v. injection (100 microg), but not i.p. injection (6-10 mg/kg) of THC. These results suggest that THC-induced impairment of spatial memory is based on the selective impairment of working memory through its effects on acquisition and retrieval processes.

Topics: Animals; Avoidance Learning; Discrimination Learning; Dronabinol; Hallucinogens; Injections, Intraventricular; Learning Disabilities; Maze Learning; Memory Disorders; Memory, Short-Term; Muscarinic Agonists; Muscarinic Antagonists; Pilocarpine; Piperidines; Pyrazoles; Rats; Rimonabant; Scopolamine

Methylenedioxymethamphetamine (MDMA) is known to damage brain pre-synaptic serotonin (5-HT) neurons. Since loss of 5-HT neurons has been implicated in memory loss, it is important to establish whether MDMA use may produce changes in postsynaptic 5-HT receptors and memory function in humans.. To investigate whether MDMA use leads to compensative alterations in post-synaptic 5-HT2A receptors and whether there is a relation with memory disturbances.. Brain cortical 5-HT2A receptor densities were studied with [123I]-5-I-R91150 SPECT in five abstinent MDMA users and nine healthy controls. Memory performance was assessed using RAVLT.. [123I]-5-I-R91150 binding ratios were significantly higher in the occipital cortex of MDMA users than in controls, indicating up-regulation. Mean cortical 5-HT2A receptor binding correlated positively with RAVLT-recall in MDMA users.. Our preliminary results may indicate altered 5-HT neuronal function with correlated memory impairment in abstinent MDMA users.

Topics: Adult; Brain; Female; Humans; Male; Memory Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Synaptic Transmission; Tomography, Emission-Computed, Single-Photon

Intracellular assessments of the physiological actions of cannabinoid receptor agonists and antagonists on adult hippocampal CA1 pyramidal cells in the in vitro slice preparation were performed using current clamp and conventional sharp-electrode intracellular recording procedures. Several manipulations were performed to delineate putative currents and conductance mechanisms affected by the cannabinoid receptor agonist WIN 55,212-2 (WIN-2). This compound produced a tonic hyperpolarization of the pyramidal cell membrane that was bicuculline sensitive, reversed by changing the chloride gradient, and abolished by the addition of TTX to the bathing medium. Instantaneous membrane input resistance, computed from hyperpolarizing current pulses (peak R(in)) was also reduced significantly in the presence of WIN-2 and was accompanied by enhancement of a superimposed slow depolarization that reduced steady-state R(in) (SSR(in)); both effects were resistant to barium. Intracellular perfusion of cesium acetate (CsAc) and the sodium/potassium channel blocker, QX314, each blocked the effect of WIN-2 on R(in) and SSR(in). WIN-2 also reduced input resistance calculated from depolarizing current injections (R(d)). This effect was also blocked by atropine, as well as media containing TTX or low Ca(2+). Each of the above effects of WIN-2 was blocked by the cannabinoid receptor antagonist SR141716A, showing a dependence on CB1 cannabinoid receptors. Several known pre- and postsynaptic processes in adult pyramidal cells are discussed which could be responsible for these cannabinoid-produced changes in membrane resistances.

Topics: Action Potentials; Animals; Benzoxazines; Calcium Channel Blockers; Hippocampus; Long-Term Potentiation; Male; Membrane Potentials; Memory Disorders; Memory, Short-Term; Morpholines; Naphthalenes; Piperidines; Pyramidal Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Time Factors

We report two patients who developed Pisa syndrome after treatment with cholinesterase inhibitors--cognition-enhancing novel agents for patients with Alzheimer's disease. Cholinergic excess could be another factor in Pisa syndrome, especially in cholinergically-imbalanced Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Donepezil; Dopamine Antagonists; Dystonia; Female; Humans; Indans; Memory Disorders; Middle Aged; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Posture; Psychomotor Agitation; Risperidone; Rivastigmine; Syndrome

Cannabinoids which impair rat working memory appear to inhibit hippocampal extracellular acetylcholine (Ach) release and reduce choline uptake through an interaction with CB1 cannabinoid receptors. Here we report that CP 55,940, a potent bicyclic synthetic cannabinoid analog, dose-dependently impaired rat performance, when given i.p. 20 min before an eight-arm radial maze test. The selective CB1 cannabinoid receptor antagonist SR 141716A, given i.p. 20 min earlier, significantly reduced the memory deficit Pretreatment with eptastigmine, a second generation cholinesterase inhibitor, given orally 100 min before the cannabinoid agonist, relieved the memory impairment without affecting CP 55,940-induced behavioural alterations such as reduced spontaneous motor activity, analgesia and hind limb splaying. These data suggest that cannabinoid-induced working memory impairment is mediated through a central cholinergic blockade.

Topics: Animals; Behavior, Animal; Cannabinoids; Cholinesterase Inhibitors; Cyclohexanols; Male; Maze Learning; Memory; Memory Disorders; Motor Activity; Physostigmine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant

The aim of this study was to investigate spatial memory and quantitative acetylcholine transporter autoradiography using a high-sensitivity imaging plate system in rats treated with beta-amyloid protein, a model of Alzheimer's disease. An eight-arm radial maze was used to evaluate spatial memory. The performance of the eight-arm radial maze task was impaired in beta-amyloid protein-treated rats. In the parietal cortex, [3H]-vesamicol binding to the vesicular acetylcholine transporter was significantly lower in beta-amyloid protein-treated rats than in vehicle-treated rats, and was significantly correlated with the mean number of correct selections in the maze task of the first 5 days in the post-operative state. These results indicate that the reduction in [3H]-vesamicol binding to vesicular acetylcholine transporter is related to memory impairment induced by beta-amyloid protein. Beta-amyloid protein-infused rats with spatial memory impairment may be useful for the development of new radiolabelled vesamicol analogues for the objective evaluation of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autoradiography; Carrier Proteins; Disease Models, Animal; Humans; Immunohistochemistry; Male; Membrane Transport Proteins; Memory Disorders; Piperidines; Quinuclidinyl Benzilate; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Synaptic Vesicles; Tissue Distribution; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

To investigate whether or not histamine was involved in scopolamine-induced spatial memory deficits evaluated in 8-arm radial maze performance of rats.. Eight-Arm radial maze performance was used to measure spatial memory in rats, and the brain regions were subsequently dissected and histamine contents were determined by HPLC.. Intracerebroventricular (icv) injection of histamine (100 or 200 ng) or thioperamide (50 micrograms), and intraperitoneal (i.p.) injection of histidine (1000 mg/kg) ameliorated memory impairment induced by scopolamine regarding both parameters of radial maze performance. 2-Thiazolylethylamine, but not 4-methylhistamine showed the similar effect to histamine. Both histamine (200 ng, icv) and histidine (1000 mg/kg, i.p.) were equally effective in increasing the histamine content in the cortex, hippocampus, and hypothalamus.. These results suggest that brain histamine plays an important role in learning and memory, and its action may be due to cholinergic neurons.

Topics: Animals; Brain; Histamine; Histamine Agonists; Histamine Antagonists; Histidine; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Piperidines; Rats; Rats, Wistar; Scopolamine; Thiazoles

The effects of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105) on the scopolamine-, electrolytic lesion of the nucleus basalis magnocellularis (NBM)-, AF64A-, baclofen-, cerebral ischemia- and electroconvulsive shock (ECS)-induced memory disruption in the passive avoidance response or radial arm maze tasks were investigated in rats. The effects of NS-105 were compared with those of aniracetam, bifemelane, idebenone, and indeloxazine in two tasks of the passive avoidance response. Furthermore, effects of NS-105 on in vivo release of acetylcholine (ACh) in the cerebral cortex, high-affinity choline uptake (HACU) of the cerebral cortex in rats with lesion of NBM, HACU of the hippocampus in rats treated with pentobarbital and activity of choline acetyltransferase (ChAT) of the cerebral cortex in rats with lesion of NBM were examined. NS-105 showed antiamnestic actions in a variety of animal models of cholinergic dysfunction employed in this study. Aniracetam improved memory disruption caused by scopolamine, but bifemelane, idebenone, and indeloxazine did not. NS-105 (10 mg/kg) showed the increase of ACh release from the cerebral cortex and the enhancement of HACU both in the cerebral cortex and hippocampus, but showed no change in activity of ChAT. NS-105 also reversed memory disruption induced by baclofen, a potent GABA(B) receptor agonist, but all of reference drugs did not. These results suggest that antiamnestic action of NS-105 is due to the facilitation of cholinergic neuronal activity and the suppression of GABA(B) receptor-mediated responses.

Topics: Acetylcholine; Animals; Avoidance Learning; Basal Ganglia; Cerebral Cortex; Cognition; Electroshock; gamma-Aminobutyric Acid; Male; Memory Disorders; Muscarinic Antagonists; Nootropic Agents; Parasympathetic Nervous System; Piperidines; Proline; Rats; Rats, Wistar; Receptors, GABA-B; Scopolamine; Synaptosomes

Memory dysfunction is a recognized and difficult to treat complication of traumatic brain injury (TBI). Since medial-temporal lobe injury is a frequent contributor to memory dysfunction in TBI, it is likely that an acetylcholine deficit contributes to memory dysfunction in this population. Recently, Donepezil, an acetylcholine-esterase inhibitor which has demonstrated a high selectivity for neural Ach-esterase (with minimal side effects), was approved for use in dementia in Alzheimer's patients. Due to its promising results in Alzheimer's patients, and reports in the literature describing the use of physostigmine (an anti-cholinesterase with significant cardiovascular and autonomic side effects) to treat memory deficits in closed head injury, we decided to begin a trial of Donepezil in two patients with TBI who were experiencing long term static memory dysfunction refractory to conventional treatment. Both patients were admitted to our facility for physical and cognitive rehabilitation, and were started on a trial of Donepezil. Modified memory tests and subjective observations by both family and staff pointed to an improvement in memory within three weeks of starting Donepezil. Should these initial results be supported in larger trials, Donepezil may prove to be a valuable tool for the treatment of memory dysfunction in TBI.

Topics: Adult; Alzheimer Disease; Brain Injuries; Cholinesterase Inhibitors; Cognitive Behavioral Therapy; Donepezil; Female; Head Injuries, Closed; Humans; Indans; Male; Memory; Memory Disorders; Mental Recall; Middle Aged; Physical Therapy Modalities; Physostigmine; Piperidines; Temporal Lobe

Intraperitoneal administration of 4-cyclohexyl-1-[(1R)-1,2-diphenylethyl]-piperazine (CDEP) immediately after the training session produced significant memory impairment in the mouse passive avoidance performance. Interestingly, this memory impairment was alleviated by subcutaneous administrations of sigma receptor agonists, (+)-N-allylnormetazocine ((+)-SKF-10,047), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and 1,3-di(2-tolyl)guanidine (DTG) immediately after the training session. In particular, the remarked recovery for this memory impairment was produced by (+)-SKF-10,047. A receptor binding study showed that CDEP possessed high affinities for both sigma 1 and sigma 2 receptor subtypes (IC50 1.4 +/- 0.3 nM for sigma 1 receptor subtype, 1.8 +/- 0.3 nM for sigma 2 receptor subtype), while (+)-SKF-10,047 had a high selectivity for the sigma 1 receptor subtype. These findings suggest that the sigma receptor, particularly sigma 1 receptor subtype, may play an important role in the CDEP-induced impairment of learning and memory processes.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Binding, Competitive; Brain Chemistry; Dopamine Agonists; Guinea Pigs; Male; Membranes; Memory Disorders; Mice; Phenazocine; Piperazines; Piperidines; Radioligand Assay; Receptors, sigma

The administration of delta9-tetrahydrocannabinol (THC), the principle psychoactive ingredient in marijuana, or the endogenous cannabinoid anandamide, has been shown to impair recent memory. The purpose of the present investigation was to determine if the cannabinoid CB1 receptor antagonist SR141716A could attenuate THC- or anandamide-induced memory impairment, and to assess the effects on memory of SR141716A alone. Memory was assessed in rats well-trained in a two-component instrumental discrimination task, consisting of a conditional discrimination, and a non-match-to-position to assess recent or working memory. SR141716A (0.0-2.0 mg/kg) had no effect on either the conditional discrimination or the non-match-to-position. However, SR141716A (0.0-2.0 mg/kg) attenuated the memory impairment produced by THC (2.0 or 4.0 mg/kg) as indexed by an enhancement of performance in the non-match-to-position. When administered to rats pretreated with anandamide (2.0 mg/kg), SR141716A (0.0-2.5 mg/kg) impaired performance in the conditional discrimination at the highest dose. This was interpreted as a deficit in some capacity unrelated to memory (e.g., motor impairment). However, lower doses of SR141716A (0.1 and 0.5 mg/kg) attenuated the anandamide-induced impairment of performance in the non-match-to-position without affecting the conditional discrimination. This is the first report that the memory impairment produced by anandamide can be attenuated by a cannabinoid antagonist; results suggest that anandamide-induced memory disruption is mediated by CB receptors.

Topics: Animals; Arachidonic Acids; Discrimination Learning; Dronabinol; Endocannabinoids; Male; Memory Disorders; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Topics: Alzheimer Disease; Animals; Carbolines; Cholinesterase Inhibitors; Humans; Memory Disorders; Nicotine; Piperidines; Rats; Receptors, Cholinergic; Receptors, GABA-A; Receptors, Nicotinic; Thiazoles