Orengedokuto and san'oshashinto improve memory deficits by inhibiting aging-dependent activation of glycogen synthase kinase-3β

10.1016/j.jtcme.2018.12.001

Hironori Fujiwara；Jun Yoshida；Dya Fita Dibwe；Suresh Awale；Haruka Hoshino；Hiroshi Kohama；Hiroyuki Arai；Yukitsuka Kudo；Kinzo Matsumoto

Alzheimer's disease ； Glycogen synthase kinase-3β ； Collapsin response mediator protein-2 ； Orengedokuto ； san'oshashinto

Journal of Traditional and Complementary Medicine

9卷4期（2019 / 10 / 01）

328 - 335

英文

Background and aim: The aging-dependent activation of glycogen synthase kinase-3β (GSK-3β) has been suggested to be important in the onset of dementia. To discover novel therapeutic Kampo medicines for dementia, we examined the effects of orengedokuto (OGT; 黃連解毒湯huáng lián jiĕdú tāng) and san'oshashinto (SST; 三黃瀉心湯sān huáng xiè xīn tāng) on memory deficits and GSK-3β activity in senescence-accelerated prone mice (SAMP8). Experimental procedure: The object recognition test (ORT) and conditioned fear memory test (CFT) were employed to elucidate short-term working memory and long-term fear memory. The activity of GSK-3β and the phosphorylation of related molecules were measured using a kinase assay and Western blotting. Results and conclusion: OGT and SST attenuated memory deficits in SAMP8 in ORT, but not in CFT. In ex vivo experiments, cortical GSK-3β activity was significantly stronger in SAMP8 than in SAMR1. The enhanced cortical GSK-3β activity in SAMP8 was accompanied by a significant increase in the level of phosphorylated collapsin response mediator protein-2 (CRMP2), an important factor that is involved in the regulation of microtubule stability. OGT and SST attenuated not only increases in cortical GSK-3β activity, but also the levels of phosphorylated CRMP2 in SAMP8. In vitro experiments, flavonoids contained in these kampo medicines, inhibited GSK-3β activity in concentration-dependent manners. These results suggest that OGT and SST prevent aging-induced short-term working memory deficits by inhibiting aging-dependent elevations in the cortical GSK-3β activity and subsequent CRMP2 phosphorylation.

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