Influences of yokukansankachimpihange on aggressive behavior of zinc-deficient mice and actions of the ingredients on excessive neural exocytosis in the hippocampus of zinc-deficient rats

Abstract

We examined the effect of Yokukansankachimpihange (YKSCH), a form of Yokukansan containing parts of two herbaceous plants, Citrus Unshiu Peel (Chimpi) and Pinellia Tuber (Hange), on aggressive behavior of mice housed individually. Mice were fed a zinc-deficient diet for 2 weeks. In a resident-intruder test, the cumulative duration of aggressive behavior was decreased in zinc-deficient mice administrated drinking water containing YKSCH (approximately 300 mg/kg body weight/day) for 2 weeks. We tested mice for geissoschizine methyl ether (GM), which is contained in Uncaria Hook, and 18β-glycyrrhetinic acid (GA), a major metabolite of glycyrrhizin contained in Glycyrrhiza, which were contained in YKS and YKSCH. In hippocampal slices from zinc-deficient rats, excess exocytosis at mossy fiber boutons induced with 60 mM KCl was attenuated in the presence of GA (100–500 µM) or GM (100 µM). The intracellular Ca2+ level, which showed an increase induced by 60 mM KCl, was also attenuated in the presence of GA (100–500 µM) or GM (100 µM). These results suggest that GA and GM ameliorate excess glutamate release from mossy fiber boutons by suppressing the increase in intracellular Ca2+ signaling. These ameliorative actions may contribute to decreasing the aggressiveness of mice individually housed under zinc deficiency, potentially by suppressing excess glutamatergic neuron activity in the hippocampus.

Pharmacological effects of yokukansan on behavioral and psychological symptoms of dementia

“…Tamano et al . also reported that geissoschizine methyl ether and 18 beta‐glycyrrhetinic acid, a major metabolite of glycyrrhizin contained in Glycyrrhiza, attenuated excess exocytosis at mossy fiber boutons induced by KCl in hippocampal slices from zinc‐deficient rats . Moreover, these compounds also attenuated the increase in intracellular Ca 2+ levels induced by KCl.…”

Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model

“…Administration of Yokukansankachimpihange, a potential herbal medicine for BPSD, to zinc-deficient mice also ameliorates social isolation-induced aggressive behavior. The two common ingredients ameliorate abnormal glutamatergic neuron activity in the hippocampus [ 100 ]. It is likely that zinc-deficient animals are models to assess the effect of drugs on behavioral abnormality, such as BPSD.…”

Yokukansankachimpihange Improves the Social Isolation-Induced Sleep Disruption and Allopregnanolone Reduction in Mice

“…Furthermore, YKSCH treatment prolongs the total sleeping time and tends to increase sleep efficacy based on polysomnography recordings in normal young healthy subjects (3). YKSCH treatment has also been reported to reduce memory impairment and BPSD-like behavior, such as hallucinations and aggressive behavior, in several rodent models (4)(5)(6)(7). Although some research using animal models have begun to elucidate the action of YKSCH in the central nervous system, little is known about how YKSCH alleviates insomnia observed in clinical practice.…”