benzofurans and Memory-Disorders

To investigate the effects of darifenacin controlled-release (CR) and oxybutynin extended-release (ER) on cognitive function (particularly memory) in older subjects.. Healthy subjects (n=150) >/=60 years were randomised to darifenacin, oxybutynin ER or placebo in a multicentre, double-blind, double-dummy, parallel-group, 3-week study. Doses were administered according to US labels: oxybutynin ER 10mg once daily (od), increasing to 15mg od then 20mg od by week 3; darifenacin 7.5mg od in weeks 1 and 2, then 15mg od in week 3. The primary end point was accuracy on the Name-Face Association Test (delayed recall) at week 3.. Results of the Name-Face Association Test at week 3 showed no significant difference between darifenacin and placebo on delayed recall (mean difference, -0.06, p=0.908). In contrast, oxybutynin ER resulted in memory impairment, with significantly lower scores than placebo and darifenacin (mean differences, -1.30, p=0.011 and -1.24, p=0.022, respectively) for delayed recall on the Name-Face Association Test at week 3. Additional tests of delayed recall indicated significant memory impairment with oxybutynin ER versus placebo at certain time points, whereas darifenacin was similar to placebo. No between-treatment differences were detected in self-rated memory, demonstrating that subjects were unaware of memory deterioration.. While darifenacin had no significant effects on memory versus placebo, oxybutynin ER caused significant memory deterioration (magnitude of effect comparable to brain aging of 10 years). The results also demonstrate that subjects may not recognise/report memory deterioration.

Topics: Aged; Analysis of Variance; Attention; Benzofurans; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Mandelic Acids; Memory Disorders; Middle Aged; Muscarinic Antagonists; Neuropsychological Tests; Psychomotor Performance; Pyrrolidines; Reaction Time; Urinary Bladder, Overactive

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/- 0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

Topics: Adult; Age Factors; Benzazepines; Benzofurans; Binding, Competitive; Carbon Radioisotopes; Dopamine Antagonists; Female; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Predictive Value of Tests; Prefrontal Cortex; Principal Component Analysis; Receptors, Dopamine D1; Schizophrenia; Tomography, Emission-Computed

Synthetic glucocorticoid administration has been reported to play a role in depression and cognitive decline. The present study investigated the 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) effects against the depressive-like behavior, memory impairment, and neurochemical alterations caused by acute dexamethasone administration in female Swiss mice. A dexamethasone dose-response curve (0.07-0.5 mg/kg, subcutaneous route, s.c.) was initially performed to validate the depressive-like behavior induction, in which the 0.25 mg/kg dose was more effective. Two experimental sets were performed to test the SeBZF1 (5 and 50 mg/kg, intragastric route, i.g.) pharmacological effect in this animal model. The 1st set revealed that the SeBZF1 reverses the dexamethasone-induced depressive-like behavior in the tail suspension test and in the splash test. In the 2nd experimental set, the compound effects of reversing the depressive-like behavior in the forced swimming test and the memory deficit in the Y-maze test induced by acute treatment with dexamethasone were demonstrated. Furthermore, SeBZF1 reversed the increase in the monoamine oxidase (MAO) activity in the prefrontal cortex (isoforms A and B) and in the hypothalamus (isoform A) caused by dexamethasone. However, no changes were observed in hippocampal MAO activity. Furthermore, animals treated with dexamethasone and SeBZF1 demonstrated a partially lower acetylcholinesterase activity in the prefrontal cortex compared with the induced group. In summary, the present study demonstrated that SeBZF1 reverses depressive-like behavior and memory deficits caused by acute dexamethasone treatment in female Swiss mice. Possibly the compound exerts its antidepressant-like action by increasing the availability of monoamines, while its effects on memory are still partially understood.

Topics: Acetylcholinesterase; Animals; Behavior, Animal; Benzofurans; Cognitive Dysfunction; Depression; Dexamethasone; Female; Memory Disorders; Mice; Monoamine Oxidase

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Benzofurans; Cecum; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Inflammation; Ligation; Male; Memory Disorders; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Punctures; Sepsis-Associated Encephalopathy; Signal Transduction; Sleep Deprivation; Survival Analysis

Previously, we designed, synthesized, and evaluated a series of quinolone-benzofuran derivatives as multitargeted anti-Alzheimer's disease (anti-AD) compounds, and we discovered that WBQ5187 possesses superior anti-AD bioactivity. In this work, we investigated the pharmacokinetics of this new molecule, as well as its therapeutic efficacy in restoring cognition and neuropathology, in the APP/PS1 mouse model of AD. Pharmacokinetic analyses demonstrated that WBQ5187 possessed rational oral bioavailability, metabolic stability, and excellent blood-brain barrier (BBB) permeability. Pharmacodynamics studies indicated that a 12-week treatment with the lead compound at doses of 40 mg/kg or higher significantly enhanced the learning and memory performance of the APP/PS1 transgenic mice, and the effect was more potent than that of clioquinol (CQ). Furthermore, WBQ5187 notably reduced cerebral β-amyloid pathology, gliosis, and neuronal cell loss and increased the levels of cAMP in the hippocampus of these mice. The surrogate measures of emesis indicated that WBQ5187 had no effect at its cognitive effective doses. Overall, our results demonstrated that this compound markedly improves cognitive and spatial memory functions in AD mice and represents a promising pharmaceutical agent with potential for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anesthetics, General; Animals; Benzofurans; Biological Availability; Blood-Brain Barrier; Brain Chemistry; Clioquinol; Cyclic AMP; Disease Models, Animal; Drug Evaluation, Preclinical; Gliosis; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nausea; Neuroprotective Agents; Phosphodiesterase 4 Inhibitors; Resorcinols; Second Messenger Systems; Vomiting

Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD.

Topics: Acetates; Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Benzofurans; Benzopyrans; Disease Models, Animal; Enzyme Inhibitors; Evoked Potentials; Gene Expression Regulation; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuronal Plasticity; Oligopeptides; Oncogene Protein v-akt; Oxadiazoles; Peptide Fragments; Reaction Time; Recognition, Psychology

L-3-n-Butylphthalide (L-NBP) exerts neuroprotective effects in animal models of cerebral ischemia, but its potential benefits in repeated cerebral ischemia-reperfusion (RCIR) injury remain unknown. We investigated the effect of L-NBP on cognitive impairment induced by RCIR in mice. Male C57Bl/6 mice received sham surgery or bilateral common carotid artery occlusion (3 times, 20 min each) and were orally administered preoperative L-NBP (30 mg/kg/day, 7 days), postoperative L-NBP (30 or 60 mg/kg/day, 28 days) or postoperative vehicle (28 days). Learning and memory were assessed by the Morris water maze task and step-down passive avoidance test. Nissl staining was used to identify pathologic changes in the hippocampal CA1 region. The expressions of proteins associated with signaling, apoptosis and autophagy were assessed by quantitative PCR and western blot. RCIR induced deficits in learning and memory that were alleviated by preoperative or postoperative L-NBP administration. Pathologic lesions in the hippocampal CA1 region induced by RCIR were less severe in mice treated with L-NBP. Preoperative or postoperative L-NBP administration in mice receiving RCIR promoted hippocampal expression of phospho-Akt and phospho-mTOR (suggesting activation of Akt/mTOR signaling), increased the Bcl-2/Bax ratio (indicating suppression of apoptosis) and reduced the LC3-II/LC3-I ratio (implying inhibition of autophagy). Preoperative or postoperative L-NBP administration also depressed hippocampal levels of beclin-1 mRNA (indicating suppression of autophagy). These findings suggest that the effect of L-NBP to alleviate learning and memory deficits in mice following RCIR may involve activation of Akt/mTOR signaling and regulation of the expressions of proteins related to apoptosis and autophagy.

Topics: Animals; Apoptosis; Autophagy; Benzofurans; Brain Ischemia; Cognition Disorders; Cognitive Dysfunction; Disease Models, Animal; Male; Memory Disorders; Mice, Inbred C57BL; Neuroprotective Agents; Proto-Oncogene Proteins c-akt; Reperfusion; TOR Serine-Threonine Kinases

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

Chronic constipation is very frequent in the general population. Although usually considered banal, this disorder has considerable personal, social and healthcare impact. Several studies have shown that the psychological impact exceeds that caused by rheumatoid arthritis or haemodialysis. Recently, prucalopride, a highly selective 5-HT4 receptor agonist has been shown to improve the symptoms of chronic constipation and to have a beneficial effect on social and healthcare impact. The drug was approved by the European Medicine Agency, in 2009 at a dose of 2 mg/day, 'for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief'. Neurological side effects or psychiatric disorders have not been reported previously with prucalopride. We present the case of a 61-year-old woman, who developed such adverse effects when given prucalopride for the treatment for chronic constipation.. A few hours after oral administration of this drug at therapeutic dose (2 mg/day), the patient experienced life-threatening neurological effects that included visual hallucination, loss of balance and memory, disorientation, exhaustion and suicidal ideation. Analysis with the Naranjo algorithm indicated a 'possible' relationship between prucalopride and these disorders.. This is the first report of prucalopride-induced neurological side effects and psychiatric disorders with prucalopride. The absence of other similar reports suggests that prucalopride rarely causes these adverse effects.

Topics: Benzofurans; Chronic Disease; Constipation; Female; Hallucinations; Humans; Memory Disorders; Mental Disorders; Middle Aged; Nervous System Diseases; Orientation; Postural Balance; Serotonin; Serotonin 5-HT4 Receptor Agonists; Suicidal Ideation

Epidemiological evidence implies a role for chronic stress and stress-related disorders in the etiopathogenesis of sporadic Alzheimer's disease (AD). Although chronic stress exposure during various stages of life has been shown to exacerbate AD-related cognitive deficits and neuropathology in AD mouse models, the role of stress exposure during the prenatal period on AD development and progression remained to be investigated. The present study therefore explored the effects of prenatal maternal stress (PMS) in both male and female APPswe/PS1dE9 mouse offspring in terms of cognition, affect, and AD-related neuropathology. As prenatal perturbations are likely to mediate their effects via alterations in epigenetic regulation, changes in hippocampal DNA methyltransferase 3a, 5-methylcytosine and 5-hydroxymethylcytosine levels were assessed as underlying mechanisms. Repetitive restraint stress during the first week of gestation exerted a sex-dependent effect, with male PMS mice showing spatial memory deficits and a blunted hypothalamus-pituitary-adrenal axis response, while female PMS mice showed improved spatial memory performance, increased depressive-like behavior, as well as a decrease in hippocampal plaque load. In addition, sex differences were observed among APPswe/PS1dE9 mice, independent of PMS (i.e., female mice showed impaired spatial memory performance, higher hippocampal plaque load, altered amyloid precursor protein processing in the CA3 and lower DNA methyltransferase 3a immunoreactivity in the dentate gyrus when compared with male mice of the same age). In conclusion, PMS exposure impacts on the behavioral phenotype and neuropathology of APPswe/PS1dE9 mice. Moreover, given the remarkable sex differences observed, one should not overlook the impact of sex-specific responses to environmental exposures when investigating gene-environment interactions in AD.

Topics: 5-Methylcytosine; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Behavioral Symptoms; Benzofurans; Cognition Disorders; Cytosine; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Female; Hippocampus; Humans; Male; Memory Disorders; Mice; Mice, Transgenic; Pregnancy; Prenatal Exposure Delayed Effects; Presenilin-1; Quinolines; Space Perception; Stress, Psychological

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

Drinking during pregnancy has been associated with learning disabilities in affected offspring. At present, there are no clinically effective pharmacotherapeutic interventions for these learning deficits. Here, we examined the effects of ABT-239, a histamine H₃ receptor antagonist, on fetal ethanol-induced fear conditioning and spatial memory deficits.. Long-Evans rat dams stably consumed a mean of 2.82 g ethanol/kg during a 4-hour period each day during pregnancy. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, litter size and birth weights were not different between the ethanol-consuming and control groups. Female adult offspring from the control and fetal alcohol-exposed (FAE) groups received saline or 1 mg ABT-239/kg 30 minutes prior to fear conditioning training. Three days later, freezing time to the context was significantly reduced in saline-treated FAE rats compared to control. Freezing time in ABT-239-treated FAE rats was not different than that in controls. In the spatial navigation study, adult male offspring received a single injection of saline or ABT-239 30 minutes prior to 12 training trials on a fixed platform version of the Morris Water Task. All rats reached the same performance asymptote on Trials 9 to 12 on Day 1. However, 4 days later, first-trial retention of platform location was significantly worse in the saline-treated FAE rats compared control offspring. Retention by ABT-239-treated FAE rats was similar to that by controls. ABT-239's effect on spatial memory retention in FAE rats was dose dependent.. These results suggest that ABT-239 administered prior to training can improve retention of acquired information by FAE offspring on more challenging versions of hippocampal-sensitive learning tasks. Further, the differential effects of ABT-239 in FAE offspring compared to controls raises questions about the impact of fetal ethanol exposure on histaminergic neurotransmission in affected offspring.

Topics: Animals; Benzofurans; Conditioning, Classical; Disease Models, Animal; Ethanol; Female; Histamine Antagonists; Learning Disabilities; Male; Memory Disorders; Nootropic Agents; Pregnancy; Prenatal Exposure Delayed Effects; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Histamine H3

This study investigated a methanol extract from the leaf and stem of Vitis amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid β protein (Aβ) (25-35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 μM Aβ (25-35) for 36 h induced neuronal apoptotic death. At concentrations of 1-10 μg/mL, V. amurensis inhibited neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS), all of which were induced by Aβ (25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 16 nmol Aβ (25-35) was inhibited by chronic treatment with V. amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G, r-2-viniferin and trans-ɛ-viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca(2+)](i) and the generation of ROS induced by Aβ (25-35) in cultured rat cortical neurons. These results suggest that the neuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the antidementia effect of V. amurensis is due to its neuroprotective effect against Aβ (25-35)-induced neurotoxicity and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Benzofurans; Cells, Cultured; Cerebral Cortex; Dibenzocycloheptenes; Dose-Response Relationship, Drug; Embryo, Mammalian; GPI-Linked Proteins; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neurons; Neuroprotective Agents; Peptide Fragments; Phytotherapy; Plant Extracts; Plant Leaves; Plant Stems; Rats; Rats, Sprague-Dawley; Resorcinols; Stilbenes; Vitis

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

3-n-Butylphthalide (NBP) may be beneficial for the treatment of ischemic stroke with multiple actions on different pathophysiological processes. In the present study, we investigated the effect of NBP isomers on learning and memory impairment induced by chronic cerebral hypoperfusion in rats. Male Wistar rats were orally administered 10 and 30 mg/kg l-, d-, or dl-NBP daily for 23 days after bilateral permanent occlusion of the common carotid arteries. Rats receiving 10 mg/kg l-NBP performed significantly better in tests for spatial learning and memory, and they had attenuated cerebral pathology, including neuronal damage, white matter rarefaction, and glial activation compared with controls. Furthermore, 10 mg/kg l-NBP-treated rats had significantly higher choline acetyltransferase activity, decreased cortical lipid peroxide, and reduced hippocampal superoxide dismutase activity, compared with vehicle controls. However, d- and dl-NBP did not show significant beneficial effects. The present findings demonstrate that the beneficial effects of l-NBP on hypoperfusion-induced cognitive deficits may be due to preventing neuropathological alterations, inhibiting oxidative damage and increasing acetylcholine synthesis. Our results strongly suggest that l-NBP has therapeutic potential for the treatment of dementia caused by decreased cerebral blood flow.

Topics: Acetylcholinesterase; Animals; Astrocytes; Benzofurans; Brain Ischemia; Carotid Artery, Common; Catalase; Cerebral Cortex; Choline O-Acetyltransferase; Cognition Disorders; Corpus Callosum; Glutathione Peroxidase; Hippocampus; Learning Disabilities; Ligation; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Visual Pathways

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D(1)R binding is increased, whereas D(2)R binding is not.

Topics: Animals; Behavior, Animal; Benzazepines; Benzofurans; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Glutamic Acid; Macaca mulatta; Male; Memory Disorders; Memory, Short-Term; Microdialysis; Positron-Emission Tomography; Prefrontal Cortex; Protein Binding; Pyrrolidines; Radioligand Assay; Receptors, Dopamine D1; Salicylamides; Time Factors; Tritium; Wakefulness

The effects of acute nicotine were determined on dopamine (DA) D(1) (D(1)R) and D(2) (D(2)R) receptor binding in the neocortex of conscious monkeys under control conditions as well as after chronic pretreatment with MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Extrastriatal neocortical D(1)R and D(2)R binding was evaluated with [(11)C]NNC112 and [(11)C]FLB457 with high-specific radioactivity using positron emission tomography (PET). Acute administration of nicotine bitartrate, given as an intravenous (i.v.) bolus plus infusion for 30 min at doses of 32 microg/kg+0.8 microg/kg/min or 100 microg/kg+2.53 microg/kg/min as base, induced slight but significant dose-dependent increases of DA in the extracellular fluid of prefrontal cortex (PFC) as determined by microdialysis. However, acute nicotine did not affect either [(11)C]NNC112 or [(11)C]FLB457 binding to D(1)R or D(2)R, respectively, in any cortical region. Chronic MK-801 (0.03 mg/kg, intramuscularly (i.m.), twice daily for 13 days) increased [(11)C]NNC112 binding to D(1)R in PFC. No significant changes were detected in [(11)C]FLB457 binding to PFC D(2)R. Although chronic MK-801 lowered baseline DA and glutamate levels in PFC, acute nicotine normalized reduced DA to control levels. Acute nicotine dose-dependently normalized the increased binding of [(11)C]NNC112 to D(1)R produced by chronic MK-801 but [(11)C]FLB457 binding to PFC D(2)R did not change. Working memory performance, impaired after chronic MK-801, was partially improved by acute nicotine. These results demonstrate that acute nicotine normalizes MK-801-induced PFC abnormality of D(1)R in PFC.

Topics: Animals; Benzazepines; Benzofurans; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamic Acid; Macaca mulatta; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Microdialysis; Nicotine; Nicotinic Agonists; Positron-Emission Tomography; Prefrontal Cortex; Pyrrolidines; Receptors, Dopamine D1; Salicylamides