Yokukansan, a Traditional Japanese Medicine, Enhances the L-DOPA-Induced Rotational Response in 6-Hydroxydopamine-Lesioned Rats: Possible Inhibition of COMT
Yokukansan, a Traditional Japanese Medicine, Enhances the L-DOPA-Induced Rotational Response in 6-Hydroxydopamine-Lesioned Rats: Possible Inhibition of COMT
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DOI：
10.1248/bpb.b15-00691
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发表时间：
2016-01-01
影响因子：
2
通讯作者：
Ikarashi, Yasushi
中科院分区：
文献类型：
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作者：
Ishida, Yasushi;Ebihara, Kosuke;Ikarashi, Yasushi
本研究旨在探讨日本传统药物育肝散（YKS）对大鼠黑质纹状体系统多巴胺（DA）功能的影响。单侧6-羟基多巴胺病变产生在大鼠黑质纹状体系统。尽管损伤侧纹状体酪氨酸羟化酶的免疫反应性明显下降，但纹状体5-羟色胺（5-HT）的免疫反应性未受影响。使用L-3，4-二羟基苯丙氨酸（L-DOPA）与苄丝肼联合治疗15天，可诱导损伤大鼠出现异常不自主运动（AIM），例如运动（旋转反应）、轴向运动、前肢运动和口舌运动。左旋多巴诱导的运动和轴向，但不是前肢和口舌，AIM显着增加和延长预管理YKS。接下来，我们研究了YKS对5-HT合成RIN 14 B细胞中由L-DOPA产生DA的影响。在L-DOPA处理后，RIN 14 B细胞产生DA及其代谢产物3-甲氧基酪胺（3-MT）。YKS显着增加DA的生产和抑制其代谢为3-MT的方式类似的儿茶酚-O-甲基转移酶（COMT）抑制剂恩他卡朋。YKS和钩藤中的某些生物碱（corynoxeine：CX，geissopropine methyl ether：GM）也抑制COMT活性，表明YKS增强L-DOPA诱导的5-HT合成细胞DA产生的作用是由于CX和GM抑制COMT所致。我们的研究结果表明，YKS促进DA补充L-多巴的效果，和COMT抑制CX和GM的贡献，至少部分，YKS的效果。
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.