dizocilpine-maleate and Dementia

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbi

Topics: Animals; Behavior, Animal; Dementia; Disease Models, Animal; Dizocilpine Maleate; Humans; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzoxazoles; Dementia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels; Humans; Male; Mice; Models, Molecular; Molecular Structure; Structure-Activity Relationship

Exaggerated thoughts, diminished mood and impaired cognition are the hallmarks of the schizophrenia-like condition. These symptoms are attributed to the dysregulation of dopamine and glutamate signaling in the brain. Since cocaine- and amphetamine-regulated transcript peptide (CART) modulates actions of dopamine as well as glutamate, we tested the role of this peptide in MK-801-induced schizophrenic dementia-like condition. MK-801-treated rats were allowed to interact with conspecific juvenile and tested for short-term (30-min) and long-term (24-h) social memory acquisition and recall. While MK-801 impaired the social interaction with a juvenile, the behavior was restored in CART [intracerebroventricular (icv) or intra-ventral tegmental area (VTA)] pre-treated animals. This action of CART was blocked by SCH23390 (dopamine D1 receptor antagonist) administered directly into the prefrontal cortex (PFC). Application of neuronal tracer Di-I in the PFC retrogradely labeled dopamine cells of the VTA, which in turn seem to receive CARTergic innervation. A significant increase in CARTimmunoreactivity was evidenced in the VTA, PFC and accumbens of the animals allowed to interact with a juvenile. However, MK-801 treatment attenuated the peptide expression and induced social memory deficits. The schizophrenic dementia-like symptoms following antagonism of glutamatergic receptors may be attributed to the reduced dopamine activity in the mesocortical system. We suggest that CART may, positively modulate the dopamine system to alleviate cognitive deficits associated with schizophrenia.

Topics: Animals; Benzazepines; Brain; Dementia; Disease Models, Animal; Dizocilpine Maleate; Male; Memory; Motor Activity; Nerve Tissue Proteins; Neurons; Psychotropic Drugs; Random Allocation; Rats, Wistar; Receptors, Dopamine D1; Schizophrenia; Schizophrenic Psychology; Social Behavior

A previous study reported biotransformation of a citrus peel polymethoxyflavone, nobiletin, by Aspergillus enabling production of 4'-demethylnobiletin, and the product's antimutagenic activity. However, the effects of fermented citrus peel on the basal forebrain-hippocampal system remain unidentified. Citrus reticulata (ponkan) fruit squeezed draffs are generated as mass waste in beverage factories. In this study using PC12D cells and cultured central nervous system neurons, we therefore examined whether Aspergillus kawachii-fermented citrus fruit squeezed draff could affect cAMP response element (CRE)- and choline acetyltransferase gene (ChAT) promoter region-mediated transcriptional activities relevant to memory formation and cholinergic function. Our current fermentation yielded approximately 80% nobiletin bioconversion, and a sample of hot-water extract of the fermented fruit squeezed draff was stronger than that of the unfermented one in facilitating CRE-mediated transcription in cultured hippocampal neurons as well as in PC12D cells. A sample of 0-80% ethanol-eluted fraction of Diaion HP-20 column-adsorbed components of the preparation obtained by the fermentation concentration-dependently and more strongly facilitated CRE-mediated transcription than did the fraction of the unfermented one in both cell culture systems. In a separate study, this polymethoxyflavone-rich fraction of the fermented fruit squeezed draff showed a potent ability to facilitate CRE-mediated and ChAT transcription in a co-culture of hippocampal neurons and basal forebrain neurons. Repeated oral gavage of mice with the fermented fraction sample prevented MK801-impaired memory formation in mice. These findings suggest that the 4'-demethylnobiletin-rich fraction prepared from the Aspergillus-fermented ponkan squeezed draff has a potential anti-dementia effect.

Topics: Animals; Aspergillus; Brain; Cell Culture Techniques; Choline O-Acetyltransferase; Citrus; Cyclic AMP Response Element-Binding Protein; Dementia; Dizocilpine Maleate; Fermentation; Flavones; Fruit; Hippocampus; Memory Disorders; Mice; Neurons; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Transcription, Genetic

The aim of the present study was to compare the cognitive enhancer potential of a recently identified highly selective α7 nicotinic receptor agonist PHA-543613 in scopolamine induced cholinergic and in MK-801 induced glutamatergic transient amnesia models in adult male Wistar rats. Spontaneous alternation paradigm in the T-maze was used as it is considered a reliable measure of spatial working memory and as T-maze performance is highly dependent on the functioning of the hippocampus and the prefrontal cortex. Scopolamine (0.5 mg/kg) and MK-801 (0.1 mg/kg) caused similar decrease of alternation rate and increased locomotion. Prior administration of PHA-543613 (1 or 3 mg/kg) dose dependently and completely reversed scopolamine induced impairment of alternation. However, PHA-543613 had lower efficacy in the MK-801 induced transient amnesia model, as the pharmacologically induced memory deficit was only partially reversed and an inverted U-shaped dose-response was found. PHA-543613 did not modulate either scopolamine or MK-801 induced increased locomotor activity or decreased choice latency. Results suggest that the α7 nicotinic receptor agonist had better efficacy to alleviate working memory deficits of rats caused by cholinergic receptor dysfunction, when NMDA receptors were not primarily targeted. On the other hand, the same memory enhancer strategy through α7 cholinergic receptors was apparently less effective when glutamatergic transmission (via NMDARs) was directly impaired by MK-801 treatment. The present results provide data supporting the need of parallel comprehensive testing of novel drug-candidates for cognitive impairment in distinct preclinical models of memory deficits.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Agonists; Cholinergic Antagonists; Dementia; Disease Models, Animal; Dizocilpine Maleate; Drug Administration Routes; Excitatory Amino Acid Antagonists; Male; Maze Learning; Quinuclidines; Rats; Rats, Wistar; Scopolamine; Spatial Memory

Topics: Animals; Citrus; Dementia; Disease Models, Animal; Dizocilpine Maleate; Flavones; Humans; Mice; Phytotherapy

Artemisia princeps var. orientalis (Compositae) is widely distributed in China, Japan and Korea and is known to have anti-inflammatory and anti-oxidative activities. The ethyl acetate fraction of ethanolic extract of A. princeps var. orientalis (AEA) was found to inhibit acetylcholinesterase activity in a dose-dependent manner in vitro (IC(50) value: 541.4 ± 67.5 μg/ml). Therefore, we investigated the effects of AEA on scopolamine-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. AEA (100 or 200 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (p < 0.05). In the Morris water maze task, AEA (200 mg/kg, p.o.) significantly shortened escape latencies in training trials and increased both swimming time spent in the target zone and probe crossing numbers during the probe trial as compared with scopolamine-treated mice (p < 0.05). Additionally, the ameliorating effect of AEA on scopolamine-induced memory impairment was antagonized by a subeffective dose of MK-801. These results suggest that AEA could be an effective treatment against cholinergic dysfunction and its effect is mediated by the enhancement of the cholinergic neurotransmitter system via NMDA receptor signaling or acetylcholinesterase inhibition.

Topics: Animals; Artemisia; Avoidance Learning; Behavior, Animal; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Receptors, N-Methyl-D-Aspartate; Scopolamine; Signal Transduction; Swimming

Our previous studies demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various rodent models of amnesia, through activation of the somatostatin neuronal system. To extend the antiamnesic action of FK960 to nonhuman primates, FK960 was evaluated for its ability to reverse the deficits in visual recognition memory produced by muscarinic cholinergic receptor blockade by scopolamine or N-methyl-D-aspartate receptor blockade by dizocilpine (MK-801) in four rhesus monkeys performing a computer-automated version of delayed nonmatching to sample, with a list length of 20 trial-unique graphic symbols. Furthermore, the effects of FK960 were compared with those of physostigmine, a cholinesterase inhibitor. Doses of FK960 (1, 3.2, 10, 32,100, 320 or 1000 microg/kg) injected i.m. 30 min before testing minimally affected visual recognition memory when administered alone. FK960 (1, 3.2, 10 or 32 microg/kg) significantly antagonized the deficits in visual recognition memory produced by scopolamine (10 microg/kg); the same doses of the drug minimally affected the deficits produced by dizocilpine (32 microg/kg). Similarly, physostigmine (3.2, 10 or 32 microg/kg) significantly and dose-dependently restored the visual recognition memory deficits produced by scopolamine (10 microg/kg) but not those produced by dizocilpine (32 microg/kg). From these results, we conclude that FK960 improves deficits in recognition memory associated with central cholinergic hypofunction in nonhuman primates, and we suggest that the therapeutic potential of this drug for patients with dementia should be evaluated.

Topics: Animals; Benzamides; Cholinesterase Inhibitors; Dementia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Macaca mulatta; Muscarinic Antagonists; Nootropic Agents; Physostigmine; Piperazines; Receptors, N-Methyl-D-Aspartate; Scopolamine; Visual Perception