Aβ(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by MI, A metabolite of protopanaxadiol-type saponins

Abstract

We previously screened neurite outgrowth activities of several Ginseng drugs in human neuroblastoma, and demonstrated that protopanaxadiol (ppd)-type saponins were active constituents. Since ppd-type saponins are known to be completely metabolized to 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol (MI) by intestinal bacteria when taken orally, MI and ginsenoside Rb 1, as a representative of ppd-type saponins, were examined for cognitive disorder. In a mouse model of Alzheimer's disease (AD) by Aβ(25-35) i.c.v. injection, impaired spatial memory was recovered by p.o. administration of ginsenoside Rb1 or MI. Although the expression levels of phosphorylated NF-H and synaptophysin were reduced in the cerebral cortex and the hippocampus of Aβ(25-35)-injected mice, their levels in ginsenoside Rb1- and MI-treated mice were almost completely recovered up to control levels. Potencies of the effects were not different between ginsenoside Rb1 and MI when given orally, suggesting that most of the ginsenoside Rb1 may be metabolized to MI, and MI is an active principal of ppd-type saponins for the memory improvement. In cultured rat cortical neurons, MI showed extension activity of axons, but not dendrites. The axon-specific outgrowth was seen even when neuritic atrophy had already progressed in response to administration of Aβ(25-35) as well as in the normal condition. These results suggest that MI has axonal extension activity in degenerated neurons, and improve memory disorder and synaptic loss induced by Aβ(25-35), MI was shown to be effective in vitro and in vivo, indicating that Ginseng drugs containing ppd-type saponins may reactivate neuronal function in AD by p.o. administration.