Yokukansan (YKS) is a traditional Japanese herbal medicine. It has been currently applied for treating behavioral and psychological symptoms of dementia in Japan. We investigated the effect of YKS on learning ability, hippocampal cell proliferation, and neural ultrastructural features in senescence-accelerated mouse prone 8 (SAMP8), a proposed animal model of Alzheimer's disease. Five-month-old male SAMP8 mice were randomly assigned to control and experimental groups. The control group had drug-free water ad libitum. The experimental mice were given 0.15% aqueous solution of YKS orally for eight weeks. Learning ability was assessed in Morris water maze test. Hippocampal cell proliferation was investigated using bromodeoxyuridine immunohistochemical method. The neural ultrastructural features, including myelin sheath and synapse, were investigated electron microscopy. Administration with YKS improved the hippocampal cell proliferation in dentate gyrus, and ameliorated learning impairment in SAMP8 mice. Numerous lipofuscin inclusions were presented in hippocampal neurons of the control mice. However, little were found after treatment with YKS. Myelin sheath was thicker and postsynaptic density length was longer after treatment with YKS. Administration with YKS ameliorated learning impairment in SAMP8 mice, mediated at least partially via delaying neuronal aging process, neurogenesis, myelin sheath and synaptic plasticity in the hippocampus. These results suggest that YKS might be effective for preventing hippocampus-dependent cognitive deficits with age.

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