T-817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory in rats infused i.c.v. with amyloid-beta peptide

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.