amiridine and Amnesia

Topics: Acridines; Aminoquinolines; Amnesia; Animals; Cholinesterase Inhibitors; Learning; Male; Memory; Nootropic Agents; Rats; Scopolamine; Tacrine

The effects of single and repeated administrations of ipidacrine (NIK-247, 9-amino-2, 3, 5, 6, 7, 8-hexahydro-1H-cyclopenta [b] quinoline monohydrochloride monohydrate) on scopolamine-induced spatial learning deficit were investigated in rats using the Morris water maze task. A single oral administration of ipidacrine (0.3 and 1 mg/kg) reduced the increased total latency induced by scopolamine in this task. The repeated administration of ipidacrine (1 mg/kg) of once a day for 5 successive days reduced the increased total latency induced by scopolamine to the levels of the saline-treated control rats in this task. In this pharmaco-kinetic study, ipidacrine was rapidly taken up into the brain within 5 min. Moreover, higher drug levels were observed mainly in the cortex and hippocampus, which both play important roles in learning and memory. Thus, a previous study together with this investigation indicate that ipidacrine improves amnesia which consists of the impairment of the working and reference memory in various animal models, suggesting that ipidacrine is a useful candidate for the therapy of patients with Alzheimer's disease.

Topics: Aminoquinolines; Amnesia; Animals; Brain; Cerebral Cortex; Cholinesterase Inhibitors; Gas Chromatography-Mass Spectrometry; Hippocampus; Learning; Male; Memory; Psychotropic Drugs; Rats; Rats, Wistar; Scopolamine

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 physostigmine, tacrine and NIK-247 on scopolamine-induced impairment of a passive avoidance response were examined in rats. In addition, we investigated possible peripheral side-effects: miosis and salivation, and central side-effects: hypothermia and tremor which are mediated by cholinergic activation. Intraperitoneal injection of physostigmine reversed scopolamine-induced amnesia at a dose of 0.03 mg/kg. Antiamnesic effects of oral administration of tacrine and NIK-247 were observed at doses of 0.3 and 0.1-0.3 mg/kg, respectively. Intraperitoneal injection of physostigmine induced miosis, salivation, hypothermia and tremor at doses > or = 0.1, 0.3, 0.3 and 1 mg/kg, respectively. Oral administration of tacrine (at doses > or = 0.3 mg/kg) and NIK-247 (at doses > or = 3 mg/kg) produced miosis. Tacrine (at doses > or = 1 mg/kg) and NIK-247 (at doses > or = 3 mg/kg) produced hypersalivation. Hypothermia and tremor were observed after administration of tacrine (at doses > or = 10 mg/kg) and NIK-247 (30 mg/kg). The antiamnesic dose of physostigmine was 1/30-1/3 of doses with central or peripheral side-effects. The dose ratio of tacrine was 1/30-1; that of NIK-247 was 1/300-1/10. These results indicate that NIK-247 has higher safety and greater selectivity for cognitive functions than physostigmine or tacrine.

Topics: Administration, Oral; Aminoquinolines; Amnesia; Animals; Avoidance Learning; Body Temperature; Cholinesterase Inhibitors; Injections, Intraperitoneal; Miosis; Physostigmine; Psychotropic Drugs; Rats; Salivation; Scopolamine; Tacrine; Tremor

The effect of NIK-247 on carbon monoxide (CO)-induced amnesia were investigated. A step-down type passive avoidance task with mice was used to compare the effects of NIK-247 with those of tacrine. Two types of CO-induced amnesia model, acute and delayed models, were used. The acute amnesia model was developed using mice exposed to CO before memory consolidation, just after training, and a retention test carried out 24 h after training. The delayed amnesia model was prepared 7 days after CO exposure even when the animals were exposed to CO 4 h after training, after memory had consolidated. NIK-247 administered post-training at 0.03-0.3 and 3 mg/kg or pre-retention test (24 h after training) at 0.3 and 10 mg/kg attenuated the acute amnesia. In addition, NIK-247 (0.03, 0.1, 1 and 10 mg/kg) and tacrine (0.03, 0.1 and 1 mg/kg) administered before the retention test (7 days after CO exposure) improved retrieval in the delayed amnesia model. Tacrine (0.01-0.3 and 3 mg/kg), administered post-training, attenuated the acute amnesia but pre-retention test administration did not. The dose-response curves for NIK-247 and tacrine were biphasic bell-shaped. These results indicated that NIK-247 has an improving effect on hypoxia-induced acute and delayed cognitive dysfunction, and suggest that NIK-247 has promise as a nootropic drug for therapy of memory deficits in patients with cerebrovascular-type dementing disorders.

Topics: Aminoquinolines; Amnesia; Animals; Avoidance Learning; Carbon Monoxide; Cholinesterase Inhibitors; Male; Mice; Psychotropic Drugs; Tacrine; Time Factors

The authors studied the influence of amiridin and tacrine on learning and memory in mice and rat by passive avoidance conditioning test at norm and under scopolamine induced amnesia as well as of their effect on acetylcholine esterase (AChE) activity in brain cortex homogenates. Amiridin in doses 0.1 and 0.2 mg/kg showed a beneficial action on conditioning in untreated animals, its effect being comparable with that of piracetam. Tacrine was ineffective. In scopolamine treated animals amiridin and tacrine showed anti-amnestic action at dose of 0.1 mg/kg which was found ineffective with respect to AChE activity. The data suggests that the ameliorating effect of amiridin and tacrine on cognitive abilities in patients with senile dementia is not related their anticholinesterase properties.

Topics: Acetylcholinesterase; Aminoquinolines; Amnesia; Animals; Cerebral Cortex; Cholinesterase Inhibitors; Dementia; In Vitro Techniques; Learning; Male; Memory; Mice; Psychotropic Drugs; Rats; Scopolamine; Tacrine

The model of amnestic syndrome obtained by treatment with scopolamine during 20 days in rats was used to study anti-amnesic activity of amiridin in comparison with that of tacrine, physostigmine and piracetam. Multiple injection of Sc resulted in significant deterioration of rats, performance in passive avoidance test. Behavioral disorders were accompanied by such changes in lipid composition of brain synaptosomes which indicated a decreased membrane fluidity. Amiridin and tacrine as well as piracetam showed anti-amnesic action which in the course of treatment correlated with their normalizing effect on lipid content of synaptosomes. The diverse effect of amiridin and tacrine with respect to physostigmine implies that the former drugs can't be attributed to anticholinesterase preparations which are traditionally used in the treatment of Alzheimer disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Amnesia; Animals; Cerebral Cortex; Cholinesterase Inhibitors; In Vitro Techniques; Lipids; Male; Physostigmine; Piracetam; Psychotropic Drugs; Rats; Scopolamine; Synaptosomes; Syndrome; Tacrine

The effects of NIK-247 [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate hydrochloride] were studied on a model involving various types of drug- and electroconvulsive shock (ECS)-induced amnesia. The step-down type passive avoidance task in mice was used for comparison of the effects with those of tacrine, a 4-aminopyridine derivative which has an antiamnesic action. NIK-247 administered pre- and post-training or pre-retention test (24 h after training) prevented the disruption of memory induced by cycloheximide administered immediately after training. In addition, NIK-247 protected from the amnesia induced by treatment with ECS, phencyclidine and picrotoxin immediately after training. Tacrine failed to protect from ECS- and PCP-induced amnesia at the doses effective on cycloheximide-induced amnesia. The results indicate that NIK-247 improves cognitive functions at different phases of the learning and memory processes such as acquisition, consolidation, and retrieval in drug- and ECS-induced amnesia. NIK-247 may produce its antiamnesic effects via the cholinergic and GABAergic neuronal systems.

Topics: Aminoquinolines; Amnesia; Animals; Avoidance Learning; Choline; Cholinesterase Inhibitors; Cycloheximide; Electroshock; gamma-Aminobutyric Acid; Male; Memory; Mice; Phencyclidine; Picrotoxin; Tacrine