Brain distribution of geissoschizine methyl ether in rats using mass spectrometry imaging analysis

Takashi Matsumoto,Mikina Takiyama,Yasushi Ikarashi,Junko Watanabe,Mitsutoshi Setou

doi:10.1038/s41598-020-63474-x

Abstract

Geissoschizine methyl ether (GM) is one of the main active ingredients responsible for ameliorating the behavioral and psychological symptoms of dementia (BPSD) in Kampo medicine yokukansan. GM is mainly metabolized into hydroxylated forms (HM-1/2). However, the brain distributions of GM and HM has not been reported in vivo. In this study, therefore, the plasma concentrations and brain distribution of these compounds were examined in vivo using rats injected intravenously with GM. Plasma concentrations were analyzed using liquid chromatography-tandem mass spectrometry analysis and brain distribution using mass spectrometry imaging analysis. Plasma GM and HM-1 concentrations decreased in the 4 h after injection, whereas the concentration of plasma HM-2 increased at 4 h. In the 0.25 h-brain, GM signals were diffusely observed throughout the brain, including the cerebral cortex, hippocampus, striatum, thalamus, amygdala, cerebellum, and cerebral ventricle. HM signals were detected only in the ventricles of the brain at 4 h. These results suggest that plasma GM enters the brain and distributes in the parenchyma of various brain regions involved in BPSD, while plasma HM does not enter the brain parenchyma. This study is also the first to visually demonstrate the brain distribution of GM and its metabolite in vivo.

Highlights

Geissoschizine methyl ether (GM) is one of the main active ingredients responsible for ameliorating the behavioral and psychological symptoms of dementia (BPSD) in Kampo medicine yokukansan
Geissoschizine methyl ether (GM) is an alkaloid derived from Uncaria hook, which is a component of YKS
Since GM is detected in the plasma and brains of rats orally administered this YKS dose[9,10], it is believed that GM contained in YKS is absorbed into the blood and reaches the brain

Summary

Introduction

Geissoschizine methyl ether (GM) is one of the main active ingredients responsible for ameliorating the behavioral and psychological symptoms of dementia (BPSD) in Kampo medicine yokukansan. The plasma concentrations and brain distribution of these compounds were examined in vivo using rats injected intravenously with GM. In vitro autoradiographic binding assays in which [3H]GM is directly exposed to normal rat brain slices revealed that GM bound to various regions appearing on the surface of brain slices[12,13] This in vitro result suggests that GM binds to the frontal cortex, hippo campus, caudate putamen, amygdala, central medial thalamic nucleus, dorsal raphe nucleus, and cerebellum. The purpose of the present study was to directly demonstrate the in vivo brain distributions of GM and its hydroxylated metabolite (HM). The distributions of GM and its metabolite HM in the brains of rats intravenously injected with GM were investigated by MSI analysis using MALDI and/or DESI. The brain distributions were assessed based on target ingredient concentrations and their time course in the plasma collected from the same animals

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Conclusion