T-817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory in rats infused i.c.v. with amyloid-beta peptide.
OBJECTIVE
Adult neurogenesis occurs throughout life in the subgranular zone and the dentate gyrus of the hippocampus. Deficient neurogenesis may be responsible for deficient hippocampal functions in neurodegenerative disorders such as Alzheimer's disease (AD). T-817MA [1-{3-[2-(1-Benzothiophen-5-yl)ethoxy] propyl}-3-azetidinol maleate] is a newly synthesized agent for AD treatment with neuroprotective effects against toxicity from amyloid-beta peptide (Abeta) and actions promoting neurite outgrowth in vitro. Furthermore, systemic administration of T-817MA ameliorated cognitive dysfunctions caused by neurodegeneration in a rat model of AD, induced by intracerebroventricular (i.c.v.) infusion of Abeta. The present study investigated quantitative relationships between spatial memory performance in Abeta-infused rats and hippocampal neurogenesis, and the effects of T-817MA on neuronal proliferation in vivo.


METHODS
Seven weeks after infusion of Abeta (peptide 1-40; 300 pmol.day(-1); i.c.v.), rats were tested in a place learning task in which they were required to alternately visit two reward places in an open field to obtain intracranial self-stimulation as rewards.


RESULTS
Rats given Abeta infusions for 10 weeks displayed spatial memory impairments and a decrease in neurogenesis compared with those infused with vehicle. Treatment of the Abeta-infused rats with T-817MA (8.4 mg.kg(-1).day(-1), p.o.) significantly increased hippocampal neurogenesis and ameliorated spatial learning impairments. Furthermore, spatial learning in the task was significantly correlated with neurogenesis.


CONCLUSIONS
These results suggest that defective hippocampal neurogenesis is a new target for AD treatment. The neurotrophic compound T-817MA increased hippocampal neurogenesis in an AD model and might be useful for treatment of AD patients.
Kimura
Tatsuo
T
System Emotional Science, Graduate School of Medicine, University of Toyama, Toyama 930-0194, Japan.
Hong Nguyen
Phuong Thi
PT
Ho
Son Anh
SA
Tran
Anh Hai
AH
Ono
Taketoshi
T
Nishijo
Hisao
H
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects*; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000502:physiology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012794:Sialic Acids / Q000096:biosynthesis; D013037:Spatial Behavior / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
C503102:1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate; D016229:Amyloid beta-Peptides; D008298:Maleates; D039842:Neural Cell Adhesion Molecule L1; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D012794:Sialic Acids; D013876:Thiophenes; C078592:amyloid beta-protein (1-40); C103469:polysialyl neural cell adhesion molecule; D001973:Bromodeoxyuridine