Recent Progress in Clinical and Basic Research of the Japanese Kampo Medicine

[Speaker] Kazushige Mizoguchi:1
1:Kampo Research & Development Division, Tsumura Kampo Research Laboratories, Tsumura & Co., Japan

Dementia is a progressive neurodegenerative disorder with cognitive dysfunction, and is often complicated by behavioral and psychological symptoms of dementia (BPSD) including excitement, aggression, and hallucinations. Typical and atypical antipsychotics are used for the treatment of BPSD, but induce adverse events. The traditional Japanese Kampo medicine yokukansan (YKS), which had been originated from the traditional Chinese medicine Yi-Gan-San, has been reported to improve BPSD without severe adverse effects.
 YKS has been approved by the Japanese Ministry of Health, Labor and Welfare, and is composed of seven medicinal herbs; Atractylodes Lancea rhizome, Poria sclerotium, Cnidium rhizome, Uncaria hook, Japanese Angelica root, Bupleurum root, and Glycyrrhiza. In 2005, Iwasaki et al. first reported that YKS improved BPSD in patients with Alzheimer's disease, vascular dementia, dementia with Lewy bodies, and other types of senile dementia in a randomized, observer-blind, controlled trial. Subsequently, this was followed by several clinical trials, and a meta-analysis of four randomized controlled trials indicated the improving effects of YKS on BPSD with almost no adverse reactions.
 In the preclinical basic studies, several lines of evidence provide that serotonergic and glutamatergic mechanisms are responsible for the clinical effects of YKS. For example, YKS ameliorated aggressiveness in rodents through serotonin (5-HT) 1A receptor stimulation and hallucinations through 5-HT2A receptor down-regulation. In addition, YKS reduced excessive glutamate concentrations through glutamate transporter activation, which mediated anti-aggressive effects.
 Geissoschizine methyl ether (GM) in Uncaria hook and 18beta-glycyrrhetinic acid (GA) in Glycyrrhiza have been identified as candidate ingredients responsible for serotonergic and glutamatergic mechanisms of YKS, respectively. Pharmacokinetic studies showed that GM and GA were detectable in the blood after oral administration of YKS in rats and humans. Moreover, both of which were determined to cross the blood-brain barrier, and reach the brain in rats orally administered YKS. Autoradiography using tritium-labeled ingredients in rats showed that GM predominantly distributed in the frontal cortex and GA in the hippocampus.
 Thus, YKS is an herbal remedy with beneficial neuropharmacological effects. In this symposium, I summarize the resent clinical and basic evidence of YKS for the treatment of BPSD.
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