Improving effects of huperzine A on spatial working memory in aged monkeysand young adult monkeys with experimental cognitive impairment

Our previous studies demonstrated that huperzine A, a reversible and select ive acetylcholinesterase inhibitor, exerts beneficial effects on memory def icits in various rodent models of amnesia. To extend the antiamnesic action of huperzine A to nonhuman primates, huperzine A was evaluated for its abi lity to reverse the deficits in spatial memory produced by scopolamine in y oung adult monkeys or those that are naturally occurring in aged monkeys us ing a delayed-response task. Scopolamine, a muscarinic receptor antagonist, dose dependently impaired performance with the highest dose (0.03 mg/kg, i .m.) producing a significant reduction in choice accuracy in young adult mo nkeys. The delayed performance changed from an average of 26.8/30 trials co rrect on saline control to an average of 20.2/30 trials correct after scopo lamine administration. Huperzine A (0.01-0.1 mg/kg, i.m.) significantly rev ersed deficits induced by scopolamine in young adult monkeys on a delayed-r esponse task; performance after an optimal dose (0.1 mg/kg) averaged 25.0/3 0 correct. In four aged monkeys, huperzine A (0.001-0.01 mg/kg, i.m.) signi ficantly increased choice accuracy from 20.5/30 on saline control to 25.2/3 0 at the optimal dose (0.001 mg/kg for two monkeys and 0.01 mg/kg for the o ther two monkeys). The beneficial effects of huperzine A on delayed-respons e performance were long lasting; monkeys remained improved for about 24 h a fter a single injection of huperzine A. This study extended the findings th at huperzine A improves the mnemonic performance requiring working memory i n monkeys, and suggests that huperzine A may be a promising agent for clini cal therapy of cognitive impairments in patients with Alzheimer's disease.