Ameliorative effects of a neuroprotective agent, T-817MA, on place learning deficits induced by continuous infusion of amyloid-beta peptide (1-40) in rats.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline due to neuronal loss and neural network dysfunction. It has been postulated that progressive neuronal loss in AD is consequence of the neurotoxic properties of the amyloid-beta peptide (Abeta). In the present study, we investigated the effect of T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy] propyl}-3-azetidinol maleate), a newly synthesized neurotrophic compound, on place learning deficits in rats with hippocampal damages. To induce granule cell loss in the dentate gyrus (DG) of the hippocampus, Abeta (1-40) was continuously infused (300 pmol/day) into the cerebral ventricle using a mini-osmotic pump for 5 weeks. Three weeks after the Abeta infusion, the rats were tested in a place learning task, which required them to alternatively visit two diametrically opposed areas in an open field to obtain intracranial self-stimulation reward. The results indicated that the Abeta-infused rats without treatment of T-817MA displayed learning impairment in the task; their performance level was significantly inferior to that of the vehicle rats. Treatment of T-817MA (8.4 mg/kg/day, p.o.) significantly improved the task performance of the Abeta-infused rats. Furthermore, T-817MA prevented granule cell loss due to Abeta-infusion, which was correlated to task performance of the rats. However, other cognitive enhancer, an acetylcholinesterase inhibitor, had no such effects. The results demonstrated that T-817MA ameliorated learning deficits induced by Abeta infusion, which might be attributed to neuroprotection in the hippocampus.
Nguyen
Phuong Thi Hong
PT
System Emotional Science, Graduate School of Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
Kimura
Tatsuo
T
Ho
Son Anh
SA
Tran
Anh Hai
AH
Ono
Taketoshi
T
Nishijo
Hisao
H
D016229:Amyloid beta-Peptides; D000818:Animals; D001507:Beclomethasone; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007859:Learning Disabilities / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000627:therapeutic use*; D009068:Movement / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013876:Thiophenes / Q000627:therapeutic use*; D013997:Time Factors
C503102:1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate; D016229:Amyloid beta-Peptides; D008298:Maleates; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D013876:Thiophenes; C078592:amyloid beta-protein (1-40); D001507:Beclomethasone