piperidines and Amnesia

Topics: Amnesia; Cholinesterase Inhibitors; Diagnostic and Statistical Manual of Mental Disorders; Donepezil; Humans; Indans; Piperidines; Syndrome; Thiamine

Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia.. Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness.. The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome.. Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways.. ClinicalTrials.gov identifier: NCT00403520.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Prodromal Symptoms

Following a 48-week, double-blind, randomized, placebo-controlled trial of donepezil in 821 patients with amnestic mild cognitive impairment (aMCI), safety and tolerability of donepezil (10 mg) were further evaluated in a 28-week extension study. Of 499 participants who completed the double-blind phase, 145 enrolled in the open-label study. Adverse events (AEs) were recorded throughout. Overall, 57.4% of participants in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE, with the most frequent treatment-emergent AEs being diarrhea, muscle spasms, insomnia, and nausea. Most were mild to moderate in severity and were more common in the first several weeks after treatment initiation. More participants in the placebo/donepezil group (22.1%) discontinued donepezil due to an AE compared with the donepezil/donepezil group (10.3%). These findings support the safety of donepezil in patients with aMCI. When compared with other studies, however, the data suggest that patients with Alzheimer's tolerate donepezil better than patients with MCI.

Topics: Adult; Aged; Aged, 80 and over; Amnesia; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nausea; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Spasm; Time Factors; Treatment Outcome

White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear.. Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression.. 55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 - 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance.. PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Atrophy; Brain; Cerebral Ventricles; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Piperidines; Prospective Studies; Temporal Lobe; Time Factors; Treatment Outcome; Vitamin E

To investigate the neurocognitive measures that best predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD).. We evaluated 539 participants with aMCI from the Alzheimer's Disease Cooperative Study clinical drug trial of donepezil, vitamin E, or placebo. During the study period of 36 months, 212 aMCI participants progressed to AD. Using progression from aMCI to AD within 36 months as the dependent variable, a generalized linear model was fit to the data using the least absolute shrinkage and selection operator. Independent variables included in this analysis were age, sex, education, APOE-e4 (APOE4) status, family history of dementia, Mini-Mental State Examination score, Digits Backwards (Wechsler Memory Scale), Maze Time and Errors, Number Cancellation, Delayed Recall of Alzheimer's Disease Assessment Scale Word List, New York University Paragraph Recall Test (Immediate and Delayed), Boston Naming Test, Category Fluency, Clock Drawing Test, and the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog).. The model that best predicted progression from aMCI to AD over 36 months included APOE4 status, the Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), and the ADAS-cog total score. When APOE4 was removed from the analysis the resulting model had a similar estimated predictive accuracy as the full model. As determined by cross-validation, the estimated predictive accuracy of the final model was 80%.. Progression from amnestic mild cognitive impairment to Alzheimer disease in this cohort was best determined by combining four common, easily administered, cognitive measures.

Topics: Age Distribution; Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Apolipoprotein E4; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Female; Genotype; Humans; Indans; Linear Models; Male; Neuropsychological Tests; Piperidines; Placebo Effect; Predictive Value of Tests; Prognosis; Sex Distribution; Vitamin E

This prospective, randomized trial was designed to test the hypothesis that continuous infusion of low-dose remifentanil can provide effective analgesia, sedation, amnesia, patient comfort and stable recovery profile without respiratory depression when compared with propofol infusion during colonoscopy.. One hundred patients were randomly assigned to receive either remifentanil (group R, 0.5 microg/kg followed by 0.05 microg/kg/min, n = 50) or propofol (group P, 0.5 mg/kg followed by 50 microg/kg/min, n = 50). Supplemental doses of remifentanil 12.5 microg in group R and propofol 10 mg in group P were given to treat complaints of moderate to severe pain and discomfort. Hemodynamic and respiratory data, pain, discomfort and sedation scores, patient and gastroenterologist satisfaction and recovery profiles were recorded.. The duration of colonoscopy was longer in group P. The mean arterial pressure, heart rate and end-tidal CO2 remained stable during the procedure and were comparable between the groups. After bolus injection of the study drugs, the respiratory rate and oxygen saturation values were lower in group R than in group P. Only one patient in group R required airway support. Pain and discomfort scores were better in group R than in group P. Sedation levels were higher in group P than in group R. Group P needed more supplemental doses than group R. The time to reach an Aldrete score of nine or more was shorter in group R, but discharge times were similar in the two groups. Amnesia was better in group P. Nausea and vomiting were more frequent in group R during the recovery phase.. Low-dose remifentanil infusion with intermittent bolus injections can provide adequate sedation, amnesia and better analgesia than propofol infusion during colonoscopy. However, remifentanil-induced nausea and vomiting may be a problem during the recovery phase.

Topics: Adolescent; Adult; Aged; Amnesia; Anesthesia, Intravenous; Anesthetics, Intravenous; Carbon Dioxide; Colonoscopy; Conscious Sedation; Double-Blind Method; Female; Hemodynamics; Humans; Hypnotics and Sedatives; Male; Midazolam; Middle Aged; Monitoring, Physiologic; Oxygen; Pain Measurement; Patient Satisfaction; Piperidines; Postoperative Nausea and Vomiting; Propofol; Prospective Studies; Remifentanil

Impairments of memory are often found after rupture and repair of aneurysms leading to a basal forebrain lesion. This open study investigated whether cholinergic substitution therapy may be a treatment option. The effect of donepezil, a cholinesterase inhibitor on memory functions was tested in an open-label, exploratory study in 11 patients with a chronic amnestic syndrome from a ruptured and repaired aneurysm of the anterior communicating artery (seven patients), the anterior cerebral (two) or the pericallosal artery (two). Mean time since onset was 75.4 months. Memory was evaluated at baseline and consecutively after 4 weeks of 5 mg donepezil daily, 8 weeks of 10 mg donepezil, and 4 weeks after drug discontinuation. Memory functions were assessed using the California Verbal Learning Test and compared with a matched group of normal, untreated controls. Tests of attention and of executive functions were also administered. Donepezil was well tolerated. Strong group effects were found at baseline and at all follow-up measurements showing profound impairments of memory functions in the patient group. Within patient statistics showed significant improvements of short and long delay free recall scores during the treatment period, both with 5 and 10 mg donepezil daily, whereas attentional and executive functions improved only non-significantly. Memory functions decreased after drug discontinuation. Repeated test administration in the control group also showed an increase of memory scores which was minor when compared with the performance change in the patient group. Donepezil may improve episodic memory functions in patients suffering from a chronic amnestic syndrome caused by rupture and repair of aneurysms of the anterior communicating, the anterior cerebral or the pericallosal artery. Future doubled-blind, placebo-controlled trials are warranted to confirm these findings.

Topics: Adult; Amnesia; Aneurysm, Ruptured; Case-Control Studies; Cholinesterase Inhibitors; Dementia; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Memory; Middle Aged; Neuropsychological Tests; Pilot Projects; Piperidines; Prosencephalon; Statistics, Nonparametric; Time Factors; Treatment Outcome

The sigma-1 (σ

Topics: Amnesia; Animals; Cell Survival; Dose-Response Relationship, Drug; Drug Development; Guinea Pigs; Humans; Ligands; Male; Mice; Models, Molecular; Molecular Structure; Piperidines; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship; Tumor Cells, Cultured

The present study was designed to evaluate the efficacy of Lactuca sativa (LS) Linn. (Asteraceae) against scopolamine-induced amnesia and to validate its traditional claim as memory enhancer.. Ethanol extract of fresh LS leaves (LSEE), standardized on the basis of quercetin content, was successively partitioned using various solvents viz., hexane, ethyl acetate, and n-butanol in increasing order of polarity. LSEE (50, 100, and 200 mg/kg) and its various fractions (at a dose equivalent to dose of LSEE exhibiting maximum activity), administered orally for 14 days, were evaluated for their memory enhancing effect against scopolamine-induced (1 mg/kg, i.p.) amnesia in 3-4 months old male Laca mice (n = 6 in each group). The memory enhancing effect was evaluated using behavioural (elevated plus maze, novel object recognition and Morris water maze tests) and biochemical parameters (acetylcholinesterase activity, malonaldehyde, superoxide dismutase, nitrite, catalase, and reduced gultathione content). The results of the test substances were compared with both scopolamine and donepezil that was used as a standard memory enhancer and acetylcholinesterase inhibitor.. Scopolamine elicit marked deterioration of memory and alteration in biochemical parameters in comparison to the control group. LSEE and its n-butanol and aqueous fractions significantly (P < 0.05) attenuated the scopolamine-induced amnesia that was evident in all the behavioural and biochemical test parameters. LSEE (200 mg/kg) and n-butanol fraction (15 mg/kg) exhibited maximum anti-amnesic effect among various tested dose levels.. The results exhibited that LS prophylaxis attenuated scopolamine-induced memory impairment through its acetylcholinesterase inhibitory and antioxidant activity validating its traditional claim.

Topics: Acetylcholinesterase; Amnesia; Animals; Antioxidants; Behavior, Animal; Catalase; Cholinergic Agents; Donepezil; Dose-Response Relationship, Drug; Glutathione; Indans; Lactuca; Male; Malondialdehyde; Maze Learning; Memory; Mice; Nitrites; Piperidines; Plant Extracts; Plant Leaves; Scopolamine; Superoxide Dismutase

Mushrooms are valued for their nutritional as well as medicinal properties. Ganoderma species are used traditionally to treat neurological disorders but scientific evidence for this is insufficient. The present study was designed to systematically evaluate the anti-amnesic effect of selected Ganoderma species i.e. G. mediosinense and G. ramosissimum. Extracts of selected mushroom species were evaluated for their antioxidant activity and acetylcholinesterase (AChE) inhibition using in-vitro assays (DPPH and Ellman tests respectively). The anti-amnesic potential of the most active extract (i.e. 70% methanol extract of G. mediosinense) was confirmed using mouse model of scopolamine-induced amnesia. Mice were treated with bioactive extract and donepezil once orally before the induction of amnesia. Cognitive functions were evaluated using passive shock avoidance (PSA) and novel object recognition (NOR) tests. The effect on brain AChE activity, brain oxidative stress (TBARS level) and neuronal damage (H & E staining) were also assessed. In-vitro results showed strong antioxidant and AChE inhibitory activities by G. mediosinense extract (GME). Therefore, it was selected for in-vivo studies. GME pre-treatment (800mg/kg, p.o.) reversed the effect of scopolamine in mice, evident by significant decrease (p <0.05) in the transfer latency time and increase in object recognition index in PSA and NOR, respectively. GME significantly reduced the brain AChE activity and oxidative stress. Histopathological examination of brain tissues showed decrease in vacuolated cytoplasm and increase in pyramidal cells in brain hippocampal and cortical regions. GME exerts anti-amnesic effect through AChE inhibition and antioxidant mechanisms.

Topics: Acetylcholinesterase; Amnesia; Animals; Antioxidants; Avoidance Learning; Behavior, Animal; Biphenyl Compounds; Brain; Cholinesterase Inhibitors; Cognition; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Ganoderma; GPI-Linked Proteins; Indans; Male; Memory; Mice; Nootropic Agents; Picrates; Piperidines; Reaction Time; Recognition, Psychology; Scopolamine; Time Factors

The ventral hippocampus (VH) has a high distribution of cannabinoid CB1 receptors which are important in modulating stress responses. Stress exposure activates the hypothalamic-pituitary-adrenal axis (HPA) which can impact hippocampal formation to change hippocampus-based memories. The purpose of the present study was to determine the possible role of the VH cannabinoid CB1 receptors in stress-induced amnesia using a step-through passive avoidance procedure in male Wistar rats. In order to induce acute stress, the animals were placed on an elevated platform for different time periods (10, 20 and 30min). Our results indicated that post-training 20 and 30min exposure to stress, but not 10min, induced amnesia. Post-training microinjection of a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 2.5-7.5ng/rat) into the VH (intra-VH) induced amnesia. Interestingly, post-training intra-VH microinjection of the same doses of ACPA improved stress-induced amnesia. On the other hand, post-training intra-VH microinjection of a selective CB1 receptor antagonist, AM-251 (20-50ng/rat) with exposure to an ineffective stress (10min) potentiated the effect of stress on memory consolidation and induced amnesia. It should be noted that post-training intra-VH microinjection of the same doses of AM-251 alone had no effect on memory consolidation. Our results revealed that post-training intra-VH microinjection of AM-251, prior to ACPA microinjection, inhibited the reversal effect of ACPA on acute elevated platform stress. Taken together, it can be concluded that exposure to post-training inescapable stress impaired memory consolidation. The impairing effects of stress on memory retrieval may be mediated by the VH cannabinoid CB1 receptors.

Topics: Amnesia; Animals; Arachidonic Acids; Hippocampus; Male; Memory Consolidation; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Stress, Psychological

The goal of this study was to evaluate the cerebroprotective and cognition-enhancing activities of the aqueous Vitex trifolia (Vt) L. (Verbenaceae) leaf extract against scopolamine-induced amnesia and in normal rats.. Reference or working memory and long-term memory in rodents were tested by experimental paradigms like passive avoidance (PA) and T-maze (TM), respectively. TM and Morris water maze (MWM) were used to screen putative spatial or localization task and the navigation memory-enhancing activities of Vt extract, respectively. In both the PA and TM models, scopolamine (0.5 mg/kg, intraperitoneal, 30 min prior to the trial) was used to induce amnesia, and donepezil (3 mg/kg/day for 15 days) was used as a standard antiamnesic drug. In MWM, two doses of Vt extract were tested against normal control rats. The aqueous Vt extract was prepared as a suspension in 0.5% carboxymethyl cellulose and administered orally at two doses (10 and 20 mg/kg/day) for 15 days to the respective group of rats.. The higher dose (20 mg/kg) of plant extract exhibited significant (p<0.01) antiamnesic activity in the PA and TM models vs. the control. In the MWM test, at probe trial, Vt extract 20 mg/kg showed the least escape latency time, which was statistically significant (p<0.01) and exhibited maximum percentage of time spent in the probe quadrant by 60.75%.. These results partly substantiate the traditional use of Vt leaves for improvement of cognition, indicating that daily administration of Vt leaves differentially could modulate short- and long-term learning and memory in rats probably through its battery of anticholinesterase, procholinergic, anti-inflammatory, antioxidant, and neuroprotective activities.

Topics: Administration, Oral; Amnesia; Animals; Cognition; Donepezil; Dose-Response Relationship, Drug; Indans; Maze Learning; Piperidines; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Scopolamine; Vitex

In this study, the effects of 5-HT4 receptors of the CA1 on MK801-induced amnesia and hyperlocomotion were examined. One-trial step-down method was used to assess memory retention and then, the hole-board method to assess exploratory behaviors. The results showed that post-training intra-CA1 administration of RS67333 (62.5 and 625 ng/mouse) and RS23597 (1 and 10 ng/mouse) decreased memory consolidation, but it did not alter head-dip counts, head-dip latency and locomotor activity. Similarly, MK801 (0.5 and 1 μg/mouse) decreased memory consolidation, but had no effect on head-dip counts and head-dip latency. Interestingly, it increased locomotor activity. The results also showed that post-training intra-CA1 injection of a sub-threshold dose of RS67333 (6.25 ng/mouse) or RS23597 (0.1 ng/mouse) could heighten MK801 induced amnesia and decrease locomotor activity, but it did not alter head-dip counts and head-dip latency. In conclusion, our findings suggest that the CA1 5-HT4 receptors are involved in MK801-induced amnesia and hyperlocomotion.

Topics: Amnesia; Aniline Compounds; Animals; CA1 Region, Hippocampal; Dizocilpine Maleate; Drug Partial Agonism; Exploratory Behavior; Male; Memory; Mice; Motor Activity; para-Aminobenzoates; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists

It is well documented that cannabinoids play an important role in certain hippocampal memory processes in rodents. On the other hand, N-Methyl-d-aspartate receptors (NMDARs) mediate the synaptic plasticity related to learning and memory processes which take place in the hippocampus. Such insights prompted us to investigate the influence of dorsal hippocampal (CA1) NMDA receptor agents on amnesia induced by cannabinoid CB1 receptor agonist, arachidonylcyclopropylamide (ACPA) in male mice. One-trial step-down passive avoidance and hole-board apparatuses were used to examine the memory retrieval and exploratory behaviors, respectively. Based on our findings, pre-training intraperitoneal (i.p.) administration of ACPA (0.01mg/kg) decreased memory acquisition. Moreover, pre-training intra-CA1 infusion of NMDA (0.001, 0.0125, 0.025 and 0.2µg/mouse), d-AP7 (0.5 and 1µg/mouse) or AM251 (50ng/mouse) impaired the memory acquisition. Meanwhile, NMDA-treated animals at the doses of 0.0005, 0.05 and 0.1µg/mouse acquired memory formation. In addition, intra-CA1 microinjection of NMDA (0.0005) plus different doses of ACPA potentiated the ACPA response, while NMDA (0.1) plus the lower or the higher dose of ACPA potentiated or restored the ACPA response, respectively. Further investigation revealed that a subthreshold dose of d-AP7 could potentiate the memory acquisition impairment induced by ACPA. Moreover, the subthreshold dose of AM251 did not alter the ACPA response, while the effective dose of the drug restored the memory acquisition impairment induced by ACPA. According to these results, we concluded that activation of the NMDA receptors in the CA1 mediates a dual effect on ACPA-induced amnesia in step-down passive avoidance learning task.

Topics: 2-Amino-5-phosphonovalerate; Amnesia; Analysis of Variance; Animals; Arachidonic Acids; Avoidance Learning; CA1 Region, Hippocampal; Cannabinoid Receptor Agonists; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Excitatory Amino Acid Antagonists; Exploratory Behavior; Male; Mice; Microinjections; N-Methylaspartate; Piperidines; Pyrazoles; Receptors, N-Methyl-D-Aspartate

Interactions between the cannabinoid and serotonin systems have been reported in many studies. In the present study, we investigated the influence of the serotonergic receptor agents on amnesia induced by the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA). Bilateral guide-cannulae were implanted to allow intra-CA3 microinjection of the drugs. The results showed that the intra-peritoneal (i.p.) injection of ACPA induce amnesia but did not alter head dip latency, head dip counts, and locomotion. Moreover, intra-CA3 injection of M-Chlorophenylbiguanide (M-CHL, a 5-HT3 serotonin receptor agonist), Y-25130 (a 5-HT3 serotonin receptor antagonist), RS67333 (a 5-HT4 serotonin receptor agonist), and RS23597-190 (a 5-HT4 serotonin receptor antagonist) impaired memory but have no effect on head dip latency and locomotor activity. In addition, intra-CA3 injection of Y-25130, RS67333, and RS23597-190 heighten the ACPA-induced amnesia and head dip counts while did not alter head dip latency and locomotor activity. On the other hand, intra-CA3 microinjection of M-CHL could not modify the ACPA-induced amnesia, head dip latency and locomotor activity whereas increased head dip counts. It can be concluded that the amnesia induced by i.p. administration of ACPA is at least partly mediated through the serotonergic receptor mechanism in the CA3 area.

Topics: Amnesia; Aniline Compounds; Animals; Arachidonic Acids; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; CA3 Region, Hippocampal; Cannabinoid Receptor Agonists; Catheters, Indwelling; Male; Mice; Oxazines; para-Aminobenzoates; Piperidines; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and β-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and β-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of β-amyloid, combined with positive results in blood-brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino)octyl)isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50=0.72 μM) that has β-amyloid anti-aggregation activity (72.5% inhibition at 10 μM) and can cross the blood-brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer's agents.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Humans; Indans; Indoles; Male; Memory; Mice; Models, Molecular; Neuroprotective Agents; Phthalimides; Piperidines; Protein Aggregates; Scopolamine; Structure-Activity Relationship

Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25-35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5mg/kg, 5mg/kg, 10mg/kg and Donepezil (DON) 1mg/kg intraperitoneally (i.p) for 14days. The last 7days of treatment regimen included daily injection of SCP 1.5mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P<0.001) and significantly decreased the acetylcholinesterase activity (P<0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P<0.001) and decreased malonaldehyde levels (P<0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P<0.001) in the SCP group. Additionally, PHL (10mg/kg) significantly enhanced the spatial memory formation (P<0.05) and neurotrophicity (P<0.001) compared to DON (1mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Animals; Antioxidants; Brain-Derived Neurotrophic Factor; Cognition Disorders; Donepezil; Glial Fibrillary Acidic Protein; Indans; Male; Maze Learning; Mice; Motor Activity; Muscarinic Agonists; Neuroprotective Agents; Nootropic Agents; Phloretin; Piperidines; Scopolamine

The present study evaluated the involvement of the dorsal hippocampal cannabinoid CB1 receptors in the combined effect of ethanol and nicotine on passive avoidance learning in adult male mice. The results indicated that pre-training administration of ethanol (1 g/kg, i.p.) impaired memory retrieval. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) or nicotine (0.5 and 0.7 mg/kg, s.c.) significantly reversed ethanol-induced amnesia, suggesting a functional interaction between ethanol and nicotine. Pre-test microinjection of a selective CB1 receptor agonist, ACPA (3 and 5 ng/mouse), plus an ineffective dose of ethanol (0.25 g/kg) or nicotine (0.3 mg/kg) improved memory retrieval, while ACPA by itself could not reverse ethanol-induced amnesia. Pre-test intra-CA1 microinjection of a selective CB1 receptor antagonist, AM251 (0.5-2 ng/mouse), did not lead to a significant change in ethanol-induced amnesia. However, pre-test intra-CA1 microinjection of AM251 prevented the ethanol (1 g/kg) or nicotine (0.7 mg/kg) response on ethanol-induced amnesia. In order to support the involvement of the dorsal hippocampal CB1 receptors in nicotine response, the scheduled mixed treatments of AM251 (0.1-1 ng/mouse), ACPA (5 ng/mouse) and nicotine (0.3 mg/kg) were used. The results indicated that AM251 reversed the response of ACPA to the interactive effects of nicotine and ethanol in passive avoidance learning. Furthermore, pre-test intra-CA1 microinjection of the same doses of ACPA or AM251 had no effect on memory retrieval. These findings show that the cannabinoid CB1 receptors of dorsal hippocampus are important in the combined effect of ethanol and nicotine on passive avoidance learning.

Topics: Amnesia; Analysis of Variance; Animals; Arachidonic Acids; Avoidance Learning; CA1 Region, Hippocampal; Drug Interactions; Ethanol; Male; Mental Recall; Mice; Microinjections; Nicotine; Piperidines; Pyrazoles; Random Allocation; Receptor, Cannabinoid, CB1

We report the case of a 74-year-old woman who presented with amnesia and positive serum anticholinergic activity (SAA), which disappeared after treatment with the cholinesterase inhibitor donepezil for 1 year. Her only other regular medications were topical glaucoma preparations. We suggest that mental stress, mild cognitive impairment and Alzheimer's disease pathology combined to generate SAA in this patient. We also consider that SAA may have subsequently become negative because of upregulation of acetylcholine production by donepezil, and because the patient's other medications and physical condition (including glaucoma) remained unchanged during the 1-year period.

Topics: Aged; Amnesia; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Female; Humans; Indans; Nootropic Agents; Piperidines

Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer's disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Amnesia; Bayes Theorem; Carbon Radioisotopes; Cognitive Dysfunction; Female; Humans; Lewy Body Disease; Male; Middle Aged; Piperidines; Positron-Emission Tomography

To evaluate the cost effectiveness of genetic screening for the apolipoprotein (APOE) ε4 allele in combination with preventive donepezil treatment in comparison with the standard of care for amnestic mild cognitive impairment (AMCI) patients in Canada.. We performed a cost-effectiveness analysis using a Markov model with a societal perspective and a time horizon of 30 years. For each strategy, we calculated quality-adjusted life-years (QALYs), using utilities from the literature. Costs were also based on the literature and, when appropriate, Ontario sources. One-way and probabilistic sensitivity analyses were performed. Expected value of perfect information (EVPI) analysis was conducted to explore the value of future research.. The base case results in our exploratory study suggest that the combination of genetic testing and preventive donepezil treatment resulted in a gain of 0.027 QALYs and an incremental cost of $1,015 (in 2009 Canadian dollars [Can$]), compared with the standard of care. The incremental cost-effectiveness ratio (ICER) for the base case was Can$38,016 per QALY. The ICER was sensitive to the effectiveness of donepezil in slowing the rate of progression to Alzheimer's disease (AD), utility in AMCI patients, and AD and donepezil treatment costs. EVPI analysis showed that additional information on these parameters would be of value.. Using presently available clinical evidence, this exploratory study illustrates that genetic testing combined with preventive donepezil treatment for AMCI patients may be economically attractive. Since our results were based on a secondary post hoc analysis, our study alone is insufficient to warrant recommending APOE genotyping in AMCI patients. Future research on the effectiveness of preventive donepezil as a targeted therapy is recommended.

Topics: Aged; Aged, 80 and over; Amnesia; Canada; Case-Control Studies; Chemoprevention; Cognitive Dysfunction; Cost-Benefit Analysis; Donepezil; Genetic Testing; Humans; Indans; Markov Chains; Molecular Targeted Therapy; Nootropic Agents; Piperidines; Precision Medicine; Quality-Adjusted Life Years; Severity of Illness Index; Standard of Care

Previous studies in our laboratory showed that cannabinoid CB1 receptor knockout mice (CB1-/-) presented increased anxiety-like behaviours that did not respond to the anxiolytic actions of benzodiazepines. These results suggest that the pharmacological effects of benzodiazepines may involve the participation of cannabinoid CB1 receptors. Therefore, the purpose of this study was to examine the effects of alprazolam and the cannabinoid CB1 receptor antagonist AM251 on behavioural assays (light-dark box test, neurological severity score and step-down inhibitory avoidance test) and on the functional activity of the CB1 receptor (WIN-55,212-stimulated [(35)S] guanosine triphosphate (GTP) gamma binding autoradiography).The administration of alprazolam (40 microg/kg, intraperitoneal (i.p.)) decreased anxiety-like behaviours in the light-dark box test and significantly reduced WIN-55,212-stimulated [(35)S]GTPgamma binding autoradiography in the amygdala and in the CA1 field of the hippocampus, but was without effects on CA2, CA3 and the dentate gyrus (DG) of the hippocampus. The administration of AM251 (3 mg/kg, i.p.) blocked the anxiolytic action of alprazolam (40 microg/kg, i.p.), significantly reduced the sedative (ataxia, neurological severity score in the 0.5 cm bar) and the amnesic actions (short time term memory (1 h after electric shock)) of alprazolam (0.5 mg/kg, i.p.).Taken together, these findings revealed that cannabinoid CB1 receptor plays a pivotal role in the pharmacological actions of benzodiazepines. Furthermore, these results suggest that blockade of cannabinoid CB1 receptors may be useful in the treatment of patients with problems related to the consumption of benzodiazepines. Further clinical trials are needed to test this hypothesis.

Topics: Alprazolam; Amnesia; Amygdala; Animals; Anti-Anxiety Agents; Anxiety; Avoidance Learning; Behavior, Animal; Benzodiazepines; CA1 Region, Hippocampal; GTP-Binding Protein gamma Subunits; Hypnotics and Sedatives; Male; Mice; Mice, Inbred ICR; Nervous System Diseases; Organ Specificity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Severity of Illness Index

Factors of error and effort in study conditions play a crucial role in the intervention for memory-impaired individuals. In the present study, efficacy of four study conditions was compared in order to elucidate the optimal study conditions: errorless/errorful and effortless/effortful.. A total of 18 patients with Alzheimer's disease and 12 patients with amnesic syndrome received study-test sessions under four different study conditions: errorless/errorful and effortless/effortful.. The errorless learning advantage was confirmed for both Alzheimer's disease and amnesic syndrome on both free recall and cued recall tests. In contrast, effortful learning was effective only for amnesic syndrome on a free recall test.. Despite the overall advantage of errorless learning, the effortful process was effective in circumscribed situations.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Cholinesterase Inhibitors; Cues; Donepezil; Female; Humans; Indans; Male; Mental Recall; Paired-Associate Learning; Pattern Recognition, Visual; Perceptual Masking; Piperidines

We report the case of a patient who presented visual hallucinations and identification disorders associated with a Capgras syndrome. During the Capgras periods, there was not only a misidentification of his wife's face, but also a more global perceptive and emotional sexual identification disorder. Thus, he had sexual intercourse with his wife's "double" without having the slightest recollection feeling of familiarity towards his "wife" and even changed his sexual habits. To the best of our knowledge, he is the only neurological patient who made his wife a mistress. Starting from this global familiarity loss, we discuss the mechanism of Capgras delusion with reference to the role of the implicit system of face recognition. Such behavior of familiarity loss not only with face but also with all intimacy aspects argues for a specific disconnection between the ventral visual pathway of face identification and the limbic system involved in emotional and episodic memory contents.

Topics: Aged; Amnesia; Antipsychotic Agents; Atrophy; Brain; Capgras Syndrome; Donepezil; Hallucinations; Humans; Indans; Male; Memory; Movement Disorders; Neuropsychological Tests; Nootropic Agents; Parkinsonian Disorders; Piperidines; Recognition, Psychology; Risperidone; Sexual Behavior; Spouses; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

LASSBio-767 [(-)-3-O-acetyl-spectaline] and LASSBio-822 [(-)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline, obtained from the flowers of Senna spectabilis (Fabaceae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase Vmax without changes in apparent Km. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with Ki of 6.1 microM and 7.5 microM, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (-)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects.

Topics: Acetylcholinesterase; Administration, Oral; Alkaloids; Amnesia; Animals; Behavior, Animal; Brain; Catalysis; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drugs, Investigational; Injections, Intraperitoneal; Kinetics; Maze Learning; Mice; Models, Molecular; Molecular Structure; Piperidines; Rats; Rats, Wistar; Scopolamine; Space Perception; Stereoisomerism

Basal forebrain cholinergic neurons and oxidative stress in brain have been suggested to play an important role in the regulation of memory functions. Therefore, the present study was planned to study the effect of donepezil, an anticholinesterase antidementia drug, insulin and melatonin, an antioxidant, on memory deficit and acetylcholinesterase (AChE) activity in brain areas of scopolamine-induced amnesic mice. Memory was tested by passive avoidance (PA) test in Swiss adult male mice. A significant increase in transfer latency time (TLT) in 2nd trial as compared to 1st trial is considered as successful learning. Scopolamine (3 mg/kg i.p.) was administered 5 min prior to 1st trial to induce amnesia. AChE activity in detergent soluble (DS) and salt soluble (SS) fractions was estimated in brain areas after completion of 2nd trial. Scopolamine was effective in producing memory impairment (amnesia) which was reverted by donepezil (5 mg/kg p.o.), insulin (1 IU/kg i.p.) and melatonin (20 mg/kg p.o.). AChE activity in DS fraction of scopolamine amnesic mice was inhibited by donepezil, insulin and melatonin with varying extent in different brain regions, whereas AChE activity in SS fraction was not much affected. The results demonstrate that anti-amnesic effect of donepezil, insulin and melatonin may be mediated through enhancement of cholinergic activity.

Topics: Acetylcholinesterase; Amnesia; Animals; Antioxidants; Avoidance Learning; Brain; Cholinergic Fibers; Donepezil; Hypoglycemic Agents; Indans; Insulin; Male; Melatonin; Mice; Motor Activity; Nootropic Agents; Piperidines; Reaction Time; Scopolamine; Transfer, Psychology

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the sigma1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and sigma1 receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Carbon Monoxide; Cholinesterase Inhibitors; Donepezil; Indans; Inhalation Exposure; Learning Disabilities; Male; Mice; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor

The acetylcholinesterase inhibitor, donepezil, is also a high affinity sigma(1) receptor agonist. We examined the involvement of sigma(1) receptors in its anti-amnesic and neuroprotective properties against amyloid beta(25-35) peptide-induced toxicity in mice.. Mice were given an intracerebroventricular (i.c.v.) injection of Abeta(25-35) peptide (9 nmol) 7-9 days before being tested for spontaneous alternation and passive avoidance. Hippocampal lipid peroxidation was measured 7 days after Abeta(25-35) injection to evaluate oxidative stress. Donepezil, the sigma(1) agonist PRE-084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti-amnesic effects, or 20 min before Abeta(25-35) injection, or 24 h after Abeta(25-35) injection and then once daily before behavioural sessions, to check their pre- and post-i.c.v. neuroprotective activity, respectively.. All the drugs tested were anti-amnesic, but only the effects of PRE-084 and donepezil were prevented by the sigma(1) antagonist BD1047. Only PRE-084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE-084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE-084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors.. The potent anti-amnesic and neuroprotective effects of donepezil against Abeta(25-35)-induced toxicity involve both its cholinergic and sigma(1) agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors.

Topics: Amnesia; Amyloid beta-Peptides; Animals; Avoidance Learning; Behavior, Animal; Donepezil; Dose-Response Relationship, Drug; Ethylenediamines; Fluorescent Dyes; Galantamine; Indans; Injections, Intraventricular; Lipid Peroxidation; Male; Maze Learning; Mice; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Phenols; Phenylcarbamates; Piperidines; Receptors, sigma; Rivastigmine; Sulfoxides; Xylenes

Five new piperidine alkaloids were designed from natural (-)-3-O-acetyl-spectaline and (-)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues (7 and 9) inhibited rat brain acetylcholinesterase, showing IC50 of 7.32 and 15.1 microM, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1mg/kg, i.p.) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds (7 and 9) did not show overt toxic effects at the doses tested in vivo.

Topics: Acetylcholinesterase; Alkaloids; Amnesia; Animals; Brain; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Flowers; Male; Mice; Molecular Structure; Muscarinic Antagonists; Piperidines; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar; Scopolamine; Structure-Activity Relationship

FK962 (N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide) is a derivative of FK960 (N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate), with putative anti-dementia properties. Here, we wanted to determine whether FK962 retained the ability of the parent compound to both facilitate somatostatinergic nerve activity in hippocampal neurons and to ameliorate cognitive dysfunction in rat models. FK962 (10(-9) - 10(- 6) M) significantly enhanced high K+-evoked somatostatin release from rat hippocampal slices. FK962 also significantly reduced somatostatin-induced inhibition of Ca2+ channels at 10(-9) - 10(-7) M in single rat hippocampal neurons using whole-cell patch-clamp. Furthermore, administration of FK962 (0.032-3.2 mg/kg, i.p.) significantly ameliorated memory deficits in passive avoidance task in animal models: scopolamine-treated rats, nucleus basalis magnocellularis-lesioned rats and aged rats. FK962 (0.01- 1) mg/kg, i.p.) significantly improved spatial memory deficits induced by nucleus basalis magnocellularis-lesion in water maze task. These results suggest that FK962 ameliorates cognitive impairment in rats via activation of the somatostatinergic nervous system in the hippocampus, indicating that FK962 could be a potent cognitive enhancer and therefore might be of therapeutic value for cognitive disorders such as Alzheimer's disease.

Topics: Aging; Amnesia; Animals; Animals, Newborn; Avoidance Learning; Basal Nucleus of Meynert; Benzamides; Calcium; Dose-Response Relationship, Drug; Hippocampus; Male; Maze Learning; Membrane Potentials; Neurons; Nootropic Agents; Patch-Clamp Techniques; Piperazines; Piperidines; Potassium; Rats; Rats, Inbred F344; Scopolamine; Somatostatin

A revisited synthesis of 2-aryl-6-methyl-1,2-dihydro-1H-pyridin-4-ones and their saturated analogues 2-aryl-6-methylpiperidin-4-ols is described. A five steps procedure, using the sulfinimine chemistry, to prepare a key intermediate beta-(6-chloronicotinic)-beta-amino ester is also reported. In vivo spontaneous working memory activity of these compounds has been investigated in the mouse. Results obtained with 2-(3-chlorophenyl)-6-methyl-1,2-dihydro-1H-pyridin-4-one 9b, the most effective derivative in this model, have been reported.

Topics: Amnesia; Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Memory, Short-Term; Mice; Molecular Structure; Piperidines; Pyridones; Scopolamine; Stereoisomerism

In the literature, there is some evidence indicating that H3 histamine receptor antagonists, in particular thioperamide, can facilitate learning and memory retrieval in laboratory rodents. The present study aimed at verifying whether this also holds for memory consolidation, a phase of memory for which there is scarcity of convincing data on the effects of H3 receptor antagonists given systemically. To that end, memory consolidation was assessed in C57BL/6J mice using the one-trial step-through inhibitory avoidance task, the compounds being injected immediately after training (foot-shock) and performance measured 24 h later. More specifically, the following effects of thioperamide (1.25-20 mg/kg) were dose-dependently analysed: (1) its potential direct effects on memory consolidation; (2) its potential reversing effects on retrograde amnesia induced by the NMDA antagonist dizocilpine (MK-801, 0.5 mg/kg) and (3) its potential reversing effects on the well-known amnesia induced by the muscarinic antagonist scopolamine (0.25 mg/kg). We found that thioperamide exerted a dose-dependent facilitative effect on memory consolidation. Furthermore, the H3 receptor antagonist reversed scopolamine- and especially dizocilpine-induced amnesia. The results strongly support the view that the brain mechanisms of memory consolidation involve a functional interaction between the NMDA and the H3 sites.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Memory; Mice; Mice, Inbred C57BL; Piperidines; Reaction Time; Scopolamine

To observe the effect of small dose donepezil (Aricept) on the cognition status and the changes of metabolites in brain tissue in patients with amnestic mild cognitive impairment (aMCI) in order to find out the effective way to prevent and cure dementia.. 33 patients with aMCI were selected. There were 21 cases in a treatment group taking 2.5 mg of Aricept daily for 3 months and 12 cases in a control group taking basic internal medicines. Before and after taking the medicine, cognition tests such as clinical memory test, basic IQ test, language fluency test and drawing-clock test were carried out. Before and after treatment, magnetic resonance spectroscopy (MRS) in hippocampus region was carried out in 5 patients of the treatment group.. Compared with the results before treatment, the memory IQ test, mini-mental state examination (MMSE) total scores as well as delayed memory scores in the treatment group were improved significantly after treatment. The difference was statistically significant. MRS results indicated that after treatment NAA/Cr and Cho/Cr in hippocampus region did not change significantly and MI/Cr was increased.. 2.5 mg/d of Aricept can improve general cognition function in patients with aMCI as shown by memory IQ and delayed memory scores. The results of MRS indicate that no apparent change of NAA/Cr and increase of MI/Cr imply improvement of memory with Aricept through activating astrocytes, stabilizing neurons and regulating the signal transmission among synapses.

Topics: Aged; Aged, 80 and over; Amnesia; Aspartic Acid; Cognition; Cognition Disorders; Creatine; Donepezil; Female; Hippocampus; Humans; Indans; Inositol; Magnetic Resonance Spectroscopy; Male; Memory; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines

Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-aminopiperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new compounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat the cognitive deficit produced by neurodegenerative pathologies like Alzheimer's disease.

Topics: Amnesia; Animals; Avoidance Learning; Chemical Phenomena; Chemistry, Physical; Cognition; Dose-Response Relationship, Drug; Indicators and Reagents; Mice; Muscarinic Antagonists; Neurodegenerative Diseases; Nootropic Agents; Piperidines; Receptors, AMPA; Scopolamine; Structure-Activity Relationship

Administration of drugs activating cannabinoid CB(1) receptors in the brain induces memory deficit in rodents, and blockade of these receptors may restore memory capacity in these animals. Central administration of beta-amyloid or beta-amyloid fragments may also lead to memory disturbances. This study was undertaken to study the involvement of cannabinoid CB(1) receptors in amnesia induced by beta-amyloid fragments in mice tested in a step-through passive avoidance paradigm. Pre-training intracerebroventricular (i.c.v.) injection of beta-amyloid fragments, beta-amyloid peptide-(25-35) (4, 8 or 16 nmol/mouse) or beta-amyloid peptide-(1-42) (200, 400, 800 pmol/mouse) 7 days prior to the learning trial reduced in a dose-dependent manner the retention of passive avoidance response. This effect was observed in two retention tests, 1 and 7 days after the learning trial. The two beta-amyloid fragments showed similar potency in reducing retention of passive avoidance behavior. This effect was counteracted by a single intraperitoneal (i.p.) injection of the cannabinoid CB(1) receptor antagonist, N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 1 mg/kg), made 30 min prior to the second retention test. The injection of SR141716A per se did not affect memory capacity of mice. The i.c.v. administration of beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) made 30 min prior to the learning trial failed to affect the retention capacity of mice as measured 1 and 7 days later. Also, the i.p. injection of SR 141716A (1 mg/kg) made 30 min prior to the learning trial did not influence the behavioral response of mice injected with beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) 7 days prior to the learning trial. These results show that beta-amyloid fragments induce a dose-dependent memory deficit. Their effect on memory retention depends upon the time of administration and seems to involve cannabinoid CB(1) receptors in the brain.

Topics: Amnesia; Amyloid beta-Peptides; Animals; Avoidance Learning; Drug Administration Schedule; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Retention, Psychology; Rimonabant; Time Factors

We examined the effect of the acetylcholinesterase (AChE) inhibitor, donepezil hydrocloride (DONP), on group II metabotropic glutamate (mGlu) receptor agonist- or antagonist-induced amnesia in the step-through passive avoidance task in male mice. DCG-IV, a group II mGlu receptor agonist, at dose of 50 ng and LY341495, a group II mGlu receptor antagonist, at dose of 300 ng, significantly attenuated the latency on the step-through task. The subcutaneous injection of DONP at dose of 1 mg/kg 1 hour before passive avoidance performance ameliorated the amnesia induced by DCG-IV and LY341495, whereas donepezil alone did not affect task latency. The results suggest that activation of group II mGlu receptors and disinhibition of the cAMP/PKA signaling pathway (caused by group II mGlu receptor antagonist) have a negative action on step-through passive avoidance memory performance, and that group II mGlu receptors and ACh interact to modulate learning and memory function.

Topics: Amino Acids; Amnesia; Animals; Avoidance Learning; Cholinesterase Inhibitors; Cyclopropanes; Donepezil; Excitatory Amino Acid Antagonists; Glycine; Indans; Male; Memory; Mice; Nootropic Agents; Piperidines; Receptors, Metabotropic Glutamate; Xanthenes

Brain histamine H(3) receptors are predominantly presynaptic and serve an important autoregulatory function for the release of histamine and other neurotransmitters. They have been implicated in a variety of brain functions, including arousal, locomotor activity, thermoregulation, food intake, and memory. The recent cloning of the H(3) receptor in our laboratory has made it possible to create a transgenic line of mice devoid of H(3) receptors. This paper provides the first description of the H(3) receptor-deficient mouse (H(3)(-/-)), including molecular and pharmacologic verification of the receptor deletion as well as phenotypic screens. The H(3)(-/-) mice showed a decrease in overall locomotion, wheel-running behavior, and body temperature during the dark phase but maintained normal circadian rhythmicity. H(3)(-/-) mice were insensitive to the wake-promoting effects of the H(3) receptor antagonist thioperamide. We also observed a slightly decreased stereotypic response to the dopamine releaser, methamphetamine, and an insensitivity to the amnesic effects of the cholinergic receptor antagonist, scopolamine. These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine.

Topics: Adjuvants, Anesthesia; Amnesia; Animals; Avoidance Learning; Brain; Dopamine; Dopamine Agents; Histamine Antagonists; Methamphetamine; Mice; Mice, Knockout; Motor Activity; Norepinephrine; Piperidines; Radioligand Assay; Receptors, Histamine H3; Running; Scopolamine; Serotonin

In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-alpha-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H3 receptor influences the acquisition and not the recall processes. We also investigated the effects of two H3 receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H3 receptor antagonism are not only mediated by relieving the inhibitory action of cortical H3 receptors, but other mechanisms are also involved. Nevertheless, H3 receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cognition; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Methylhistamines; Pattern Recognition, Visual; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Scopolamine; Thiourea

In the present study a short (120 min) and long-lasting (360 min) antagonism of scopolamine-induced amnesia in rats was investigated in an eight-arm radial maze, by (3a S, 8a R)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-o l[8-(cis2,6-dimethyl-morpholin-4-yl)octyl]-carbamate L-bitartrate hydrate (MF268), a new cholinesterase inhibitor. Upon completing the training session, the rats were orally administered increasing doses of MF268 (2, 3, 6, 7, and 8 mg/kg) 60 min prior to s.c. injection of scopolamine (0.25 mg/kg). Following a further 60 min the rat was placed in the maze. The reversal of scopolamine-induced impairment was characterized by an inverted U-shaped dose-response curve. A significant reduction in the number of errors, and time taken to complete the maze was observed with a dose of 6 mg/kg. The compound improved memory retention without affecting scopolamine-induced hypermotility. When the same dose was administered 360 min prior to the test a significant reduction in the number of amnesic animals was observed, whereas no cognitive improvement was detected when either 1-Benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine hydrochloride (E2020) (0.25 mg/kg) or tacrine (0.5 mg/kg) were administered 360 min prior to the test. The kinetics of whole-brain cholinesterase confirmed the long-lasting activity for MF268. A clinical relevance for the use of MF268 in AD treatment is suggested.

Topics: Amnesia; Animals; Brain; Cholinesterase Inhibitors; Cognition; Donepezil; Indans; Male; Maze Learning; Morpholines; Motor Activity; Muscarinic Antagonists; Piperidines; Rats; Rats, Wistar; Scopolamine; Tacrine

The effects of (-)-huperzine A ((5R,9R,11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5, 9-methanocycloocta[b]pyridin-2(1H)-one), and of the hydrochloride salt of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine) and tacrine (9-amino-1,2,3,4-tetrahydroacridine), on the scopolamine-induced memory deficits in rats were compared in a radial maze, using a 4-out-of-8 baiting procedure. Scopolamine (0.15 mg/kg, i.p.) caused significant impairment in the rats' ability to fulfil the radial maze task. (-)-Huperzine A (0.2-0.4 mg/kg, p.o.; 0.1-0.4 mg/kg, i.p.) had greater efficacy than E2020 (0.6-0.9 mg/kg, p.o.; 0.3-0.6 mg/kg, i.p.) and tacrine (1.5-2.5 mg/kg, p.o.; 0.3-0.6 mg/kg, i.p.) on the improvement of scopolamine-induced working and reference memory errors, respectively. There appeared to be an inverse bell-shape dose-dependent effect for all three compounds tested. The compared data demonstrate that (-)-huperzine A is the most potent and orally active acetylcholinesterase inhibitor of the three, and fits more closely the established criterions for an ideal acetylcholinesterase inhibitor to be used in clinical studies.

Topics: Alkaloids; Amnesia; Animals; Cholinesterase Inhibitors; Donepezil; Indans; Male; Maze Learning; Muscarinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Scopolamine; Sesquiterpenes; Tacrine

The effects of NIK-247 on cholinesterase, scopolamine-induced amnesia and spontaneous movement were examined and compared with those of the well-known cholinesterase inhibitors tacrine and E-2020. NIK-247, tacrine and E-2020 all strongly inhibited acetylcholinesterase (AChE) in human red blood cells (IC50s = 1.0 x 10(-6), 2.9 x 10(-7) and 3.7 x 10(-8) M, respectively). In addition, NIK-247 and tacrine, but not E-2020, strongly inhibited butyrylcholinestrase (BuChE) in human serum. All three drugs produced mixed inhibition of AChE activity. Moreover, the inhibitory effect of NIK-247 on AChE was reversible. All compounds at 0.1-1 mg/kg p.o. significantly improved the amnesia induced by scopolamine (0.5 mg/kg s.c.) in rats performing a passive avoidance task. The three compounds at 1 and 3 mg/kg p.o. did not significantly decrease spontaneous movement by rats. These findings suggest that NIK-247 at a low dose (0.1-1 mg/kg p.o.) improves scopolamine-induced amnesia but does not affect spontaneous movement. The findings suggest that NIK-247 may be a useful drug for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amnesia; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Motor Activity; Piperidines; Psychotropic Drugs; Rats; Rats, Wistar; Scopolamine; Tacrine

The effects of the administration of metoclopramide, cisapride and SR-17 on memory processes were evaluated in the mouse passive avoidance test. The administration of dicyclomine (0.1-3 mg kg-1 i.p.), immediately after termination of the training session, produced a dose-dependent amnesic effect. Metoclopramide (1-5 mg kg-1 i.p.), cisapride (0.5-2 mg kg-1 i.p.) and SR-17 (1-10 mg kg-1 i.p.), administered 20 min before the training session, prevented dicyclomine-induced amnesia. In the same experimental conditions piracetam (30 mg kg-1 i.p.), physostigmine (0.2 mg kg-1 i.p.) and CGP 35348 (100 mg kg-1 i.p.) prevented dicyclomine amnesia. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota-rod test, nor did they modify spontaneous motility, as revealed by the Animex test. These results suggest that metoclopramide, cisapride and SR-17 play an important role in the modulation of memory processes. On these bases, these compounds could be useful in the treatment of cognitive deficits.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Benzofurans; Bridged Bicyclo Compounds; Cisapride; Dicyclomine; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Memory; Metoclopramide; Mice; Motor Activity; Muscarinic Antagonists; Piperidines; Serotonin Antagonists; Serotonin Receptor Agonists

The potential of heptylphysostigmine tartrate (pyrrolo [2,3b] indol-5-ol, 3,3a,8,8a-hexahydro-1,3a,8-trimethylheptylcarbamate [ester, (3aS-cis)]) (MF201), a new second-generation cholinesterase inhibitor, to antagonize scopolamine-induced amnesia in rats was assessed in an 8-arm radial maze. Upon completing the training session, the rats were orally administered increasing doses of MF201 (2, 3, 4, 6 and 8 mg/kg) 60 min prior to a s.c. injection of scopolamine (0.25 mg/kg). 9-Amino-1,2,3,4-tetrahydroamino-acridine hydrochloride hydrate (tacrine) (0.25, 0.37, 0.5, 1 and 2 mg/kg), 1-benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine (E2020) (0.125, 0.18, 0.25 and 0.5 mg/kg) and physostigmine (0.15, 0.25, 0.5 and 1 mg/kg) were orally administered and rats were tested in the same task. As previously described, scopolamine induced an impairment in radial maze performance, measured in terms of total number of errors, total time taken to complete the task and the percentage of amnesic animals. The reversal of scopolamine-induced impairment was characterized by the presence of an inverted U-shaped dose-response curve. A significant antagonistic effect was achieved with a dose (mg/kg) of 0.25 for E2020, 0.5 for tacrine and physostigmine and 3, 4 and 6 for MF201, the latter manifesting a broader spectrum of activity (3-6 mg/kg). While the maximal active doses restored the scopolamine-induced modified pattern of arm entry, they were ineffective in reducing hypermotility, suggesting the drugs have a specific effect on cognitive function.

Topics: Amnesia; Analysis of Variance; Animals; Behavior, Animal; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Indans; Male; Maze Learning; Motor Activity; Muscarinic Antagonists; Physostigmine; Piperidines; Rats; Rats, Wistar; Scopolamine; Tacrine

The effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease.

Topics: Acetylcholinesterase; Alkaloids; Amnesia; Animals; Butyrylcholinesterase; Cerebral Cortex; Cholinergic Antagonists; Cholinesterase Inhibitors; Donepezil; Indans; Kinetics; Male; Maze Learning; Memory; Memory, Short-Term; Piperidines; Rats; Rats, Sprague-Dawley; Scopolamine; Sesquiterpenes; Tacrine

Three sigma receptor ligands were examined for their ameliorating effects on p-chloroamphetamine-induced amnesia in mice. p-Chloroamphetamine was administered intraperitoneally 30 min before the training session of the passive avoidance response. Each sigma receptor ligand was administered 60 min before or immediately after the training session, or 60 min before the retention test. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype benzomorphan sigma receptor ligand, significantly reduced the p-chloroamphetamine-induced amnesia in these three administration schedules, as do acetylcholinesterase inhibitors. On the contrary, the significant anti-amnesic effects elicited by non-benzomorphan sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) or (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), were observed depending upon the timing of their administration. In addition, the ameliorating effect of (+)-SKF-10,047 against the p-chloroamphetamine-induced amnesia was superior to that of (-)-SKF-10,047. The (+)-SKF-10,047-induced anti-amnesic effect was significantly antagonized by the concurrent administration of either scopolamine, a muscarinic receptor antagonist, or hemicholinium-3, an inhibitor of the Na(+)-dependent high-affinity choline uptake site. These findings indicated that sigma receptor ligands had anti-amnesic effects against drug-induced memory impairment. In addition, the anti-amnesic effect of (+)-SKF-10,047 was superior to those of other sigma receptor ligands, and was mediated by both the sigma receptor and the central acetylcholinergic system.

Topics: Acetylcholine; Amnesia; Animals; Anticonvulsants; Avoidance Learning; Brain; Cholinesterase Inhibitors; Dopamine Agonists; Electroshock; Guanidines; Ligands; Male; Memory; Mice; Mice, Inbred Strains; p-Chloroamphetamine; Phenazocine; Piperidines; Receptors, sigma; Serotonin Antagonists

A series of 1-ar(o)yl-3-[2-(1-benzyl-4-piperidinyl)ethyl](thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridyl group. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio)urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.

Topics: Acetylcholinesterase; Amnesia; Animals; Avoidance Learning; Cholinesterase Inhibitors; Dementia; Dose-Response Relationship, Drug; Hydrogen Bonding; Mice; Molecular Conformation; Molecular Structure; Piperidines; Rats; Scopolamine; Structure-Activity Relationship; Thiourea

We studied the effects of a selective inhibitor of protein kinase C (PKC), 2,6-diamino-N-[(1-(1-oxotridecyl)-2-piperidinyl]methyl)hexamide (NPC 15437), on acquisition and memory retention of a Y-maze avoidance task in mice. Post-training administration of NPC 15437 (0.1-10 mg/kg i.p.) induced a dose-dependent deficit in retention of the temporal but not the spatial component of the task. This selective amnesia does not reflect state dependence and NPC 15437 (1 mg/kg) had no effect on acquisition and memory retrieval. Our results suggest that this new PKC inhibitor interferes with mechanisms underlying memory consolidation. This is in agreement with recent findings suggesting that PKC is involved in memory processes.

Topics: Amnesia; Animals; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Memory; Mice; Piperidines; Protein Kinase C; Receptors, N-Methyl-D-Aspartate

JO 1784 ((+)-N-Cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride), has been recently described as a selective ligand for the sigma receptor with an IC50 of 39 +/- 8 nM28. In the present study the effects of JO 1784 on experimental induced amnesia were investigated using one trial passive avoidance task in rats. Amnesia was produced by injecting scopolamine (1 mg/kg i.p.) 30 min before the second session (T2) on day 2 of the passive avoidance task. The anti-amnesic effect of JO 1784 was compared with other typical and atypical psychotropic drugs which interact at the sigma and or the phencyclidine site. JO 1784 was studied at 5 doses; 0.0625, 0.25, 1.0, 4.0 and 16.0 mg/kg i.p. ((+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine ((+)-3-PPP). Rimcazole, (+)-N-allylnormetazocine ((+)-NANM), 1,3-di(2-tolyl) guanidine (DTG) were studied at 4 doses; 0.25, 1.0, 4.0 and 8.0 mg/kg i.p. All drugs were administered 60 min before the test (T2) on day 2 i.e. 30 min before scopolamine. Piracetam (1000 mg/kg p.o.) administered in the same test conditions was used as a reference compound in each experiment. Of the drugs investigated JO 1784 (0.25, 1.0, 4.0 and 16.0 mg/kg i.p.), (+)-3-PPP (0.25, 1.0 and 4.0 mg/kg i.p.), DTG (1.0, 4.0 and 8.0 mg/kg) and piracetam significantly reversed scopolamine induced amnesia on day 3 (T3). At the lower dose, JO 1784 (0.0625 mg/kg) failed to reverse the amnesic effects of scopolamine on day 3. These results suggest that JO 1784 the selective sigma ligand, may be beneficial in amnesic status.

Topics: Amnesia; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Carbazoles; Cinnamates; Cyclopropanes; Dopamine Agents; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Scopolamine

A role played by serotonergic neuronal system in cycloheximide (CXM)-induced amnesia was studied in mice using a step-down passive avoidance task. CXM (30 mg/kg SC) given immediately after training caused impairment of memory. Nonselective serotonin (5-HT) antagonist methysergide and selective 5-HT2 antagonist ritanserin significantly attenuated impairment of memory caused by CXM. 5-HT1 antagonist (+/-)-pindolol had no effect on CXM-induced amnesia. The antiamnesic effect of ritanserin on CXM-induced amnesia was antagonized by 5-HT (ICV), but not by nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine and 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin at the dose level which did not cause the memory disruption. Scopolamine antagonized the antiamnesic effects of methysergide and ritanserin on CXM-induced amnesia. These results suggest that 5-HT2 receptors and cholinergic neuronal system may play an important role in memory formation.

Topics: Amnesia; Animals; Cycloheximide; Male; Methysergide; Mice; Piperidines; Receptors, Serotonin; Ritanserin; Scopolamine

The effects of minaprine on cycloheximide-induced amnesia were investigated in a step-down passive avoidance task in mice. Minaprine significantly improved cycloheximide-induced amnesia. This effect was inhibited by scopolamine, but was potentiated by physostigmine. The anti-amnesic effect of minaprine on the cycloheximide-induced memory impairment was also antagonized by a serotonin (5-HT) releaser, p-chloroamphetamine, and by a 5-HT precursor, 5-hydroxytryptophan, whereas a 5-HT1A-selective agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, was inactive. The memory-improving effect of minaprine on cycloheximide-induced amnesia was potentiated by a selective 5-HT2 antagonist, ritanserin. These results suggest that the beneficial effect of minaprine on cycloheximide-induced amnesia may be related not only to cholinergic but also serotonergic neuronal systems (5-HT2 receptors).

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amnesia; Animals; Avoidance Learning; Cycloheximide; Drug Interactions; Male; Mice; p-Chloroamphetamine; Physostigmine; Piperidines; Pyridazines; Ritanserin; Scopolamine; Tetrahydronaphthalenes

Earlier investigations of sympathomimetic drugs overcoming the amnesic action of cycloheximide (CXM) in day-old chickens were extended to biochemical studies in vitro. The effects of amphetamine, norepinephrine, alpha and beta noradrenergic stimulants and receptor blockers on Na+/K+ ATP'ase activity in total homogenate of chicken forebrain were investigated. Norepinephrine and the beta stimulant, isoprenaline significantly stimulated the activity of this enzyme, while the beta blocker, propranolol inhibited activity. Amphetamine, the alpha stimulant, methoxamine and the alpha receptor blocker, piperoxane had no effect on Na/K+ ATP'ase activity in total homogenate. In a purified synaptosomal preparation, both amphetamine (5 X 10(-5) M) and norepinephrine (1 X 10(-4) M) produced a slight stimulation of Na+/K+ ATP'ase activity. A similar concentration of amphetamine (1.12 X 10(-4) M) did not inhibit 14C-leucine uptake or incorporation into protein in the synaptosomal fraction. Nor was it able to alleviate CXM inhibition of 14C-leucine incorporation into synaptosomal protein. The results are interpreted in terms of amphetamine (via release of norepinephrine) norepinephrine and isoprenaline stimulating and maintaining the labile, sodium pump-dependent, phase of memory formation for a sufficient length of time until protein synthesis inhibition by CXM wears off.

Topics: Adenosine Triphosphatases; Amnesia; Amphetamines; Animals; Brain; Chickens; Cycloheximide; Enzyme Activation; Humans; Isoproterenol; Male; Methoxamine; Norepinephrine; Ouabain; Piperidines; Piperoxan; Potassium; Propranolol; Protein Biosynthesis; Sodium; Synaptosomes

Topics: Amitriptyline; Amnesia; Animals; Brain Chemistry; Electroshock; Humans; Injections, Intraperitoneal; Male; Memory; Mice; Nialamide; Piperidines; Serotonin