Ishida Yasushi, Ebihara Kosuke, Tabuchi Masahiro, Imamura Sachiko, Sekiguchi Kyoji, Mizoguchi Kazushige, Kase Yoshio, Koganemaru Go, Abe Hiroshi, Ikarashi Yasushi
Department of Psychiatry, Faculty of Medicine, University of Miyazaki.
Biol Pharm Bull. 2016;39(1):104-13. doi: 10.1248/bpb.b15-00691.
The aim of the present study was to investigate the effects of the traditional Japanese medicine yokukansan (YKS) on the function of dopamine (DA) in the rat nigrostriatal system. Unilateral 6-hydroxydopamine lesions were produced in the rat nigrostriatal system. Despite a marked loss in the striatal immunoreactivity of tyrosine hydroxylase on the lesion side, striatal serotonin (5-HT) immunoreactivity was not affected. Treatment using L-3,4-dihydroxyphenylalanine (L-DOPA) in conjunction with benserazide for 15 d induced abnormal involuntary movements (AIMs) such as locomotive (rotational response), axial, forelimb, and orolingual movements in the lesioned rats. The L-DOPA-induced locomotive and axial, but not forelimb and orolingual, AIMs were significantly increased and prolonged by the pre-administration of YKS. We next investigated the effects of YKS on the production of DA from L-DOPA in 5-HT synthetic RIN 14B cells. RIN 14B cells produced DA and its metabolite, 3-methoxytyramine (3-MT), following L-DOPA treatment. YKS significantly augmented DA production and inhibited its metabolism to 3-MT in a manner similar to the catechol-O-methyltransferase (COMT) inhibitor entacapone. YKS and some alkaloids (corynoxeine: CX, geissoschizine methyl ether: GM) in Uncaria hook, a constituent herb of YKS, also inhibited COMT activity, indicating that the augmenting effect of YKS on L-DOPA-induced DA production in 5-HT synthetic cells was due to the inhibition of COMT by CX and GM. Our results suggest that YKS facilitates the DA supplemental effect of L-DOPA, and that COMT inhibition by CX and GM contributes, at least in part, to the effects of YKS.
本研究的目的是探讨传统日本药物 yokukansan（YKS）对大鼠黑质纹状体系统中多巴胺（DA）功能的影响。在大鼠黑质纹状体系统中制造单侧 6-羟基多巴胺损伤。尽管损伤侧纹状体酪氨酸羟化酶的免疫反应性显著丧失，但纹状体 5-羟色胺（5-HT）免疫反应性未受影响。使用左旋多巴（L-DOPA）联合苄丝肼治疗 15 天可诱导损伤大鼠出现异常不自主运动（AIMs），如运动性（旋转反应）、轴向、前肢和口面部运动。预先给予 YKS 可使 L-DOPA 诱导的运动性和轴向 AIMs 显著增加并延长，但前肢和口面部 AIMs 不受影响。接下来，我们研究了 YKS 对 5-HT 合成 RIN 14B 细胞中 L-DOPA 生成 DA 的影响。L-DOPA 处理后，RIN 14B 细胞产生 DA 及其代谢产物 3-甲氧基酪胺（3-MT）。YKS 以类似于儿茶酚-O-甲基转移酶（COMT）抑制剂恩他卡朋的方式显著增加 DA 的生成并抑制其代谢为 3-MT。YKS 及其成分草药钩藤中的一些生物碱（钩藤碱：CX，异钩藤碱甲醚：GM）也抑制 COMT 活性，表明 YKS 对 5-HT 合成细胞中 L-DOPA 诱导的 DA 生成的增强作用是由于 CX 和 GM 对 COMT 的抑制作用。我们的结果表明，YKS 促进了 L-DOPA 的 DA 补充作用，并且 CX 和 GM 对 COMT 的抑制至少部分促成了 YKS 的作用。
