Männistö P T, Tuomainen P, Toivonen M, Törnwall M, Kaakkola S
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
J Neural Transm Park Dis Dement Sect. 1990;2(1):31-43. doi: 10.1007/BF02251244.
Interactions between a selective catechol-O-methyltransferase (COMT) inhibitor OR-462 and a monoamine oxidase (MAO)-A inhibitor clorgyline were studied measuring concentrations of L-dopa, dopamine and their metabolites in the rat hypothalamus and striatum after administration of levodopa/carbidopa (15/30 mg/kg i.p.). Part of the experiments were performed in rats pretreated with 6-OH-dopamine (6-OHDA) intracerebroventricularly (i.c.v.) to determine whether changes in dopamine metabolism occurred inside or outside catecholaminergic neurons. OR-462 was an effective COMT inhibitor at the doses 3 and 30 mg/kg i.p. Inhibition of 3-O-methyldopa (3-OMD) formation from L-dopa was reflected in the hypothalamus (45-81% decrease) and striatum (87-88% decrease), since 3-OMD penetrates the blood-brain barrier. Homovanillic acid (HVA) was decreased only in the striatum at 30 mg/kg of OR-462. Clorgyline (8 and 32 mg/kg i.p.) decreased 3,4-dihydroxyphenylacetic acid (DOPAC) formation in the hypothalamus and striatum by 61-91%. When given together, OR-462 and clorgyline elevated hypothalamic dopamine levels 3.2-4.6-fold, but striatal dopamine only 1.3-1.9-fold. The formation of 3-OMD and DOPAC remained suppressed and even brain HVA levels were decreased by 51-97%. 6-OHDA treatment decreased striatal and hypothalamic dopamine by 50% and noradrenaline by 75%. In these animals levodopa/carbidopa increased brain L-dopa 2.4-4-fold, those of 3-OMD 1.2-1.7-fold compared to intact animals, but the synthesis and metabolism of dopamine and the effects of COMT and MAO inhibitors were not significantly changed. Levodopa/carbidopa treatment decreased significantly prolactin and thyrotropin levels in serum but none of the additional treatments changed this action.
研究了选择性儿茶酚-O-甲基转移酶（COMT）抑制剂OR-462与单胺氧化酶（MAO）-A抑制剂氯吉兰之间的相互作用，通过测量左旋多巴/卡比多巴（15/30mg/kg腹腔注射）给药后大鼠下丘脑和纹状体中左旋多巴、多巴胺及其代谢产物的浓度来进行研究。部分实验在经脑室内（i.c.v.）注射6-羟基多巴胺（6-OHDA）预处理的大鼠中进行，以确定多巴胺代谢的变化是发生在儿茶酚胺能神经元内部还是外部。OR-462在3mg/kg和30mg/kg腹腔注射剂量下是一种有效的COMT抑制剂。由于3-O-甲基多巴（3-OMD）可穿透血脑屏障，其在下丘脑（降低45-81%）和纹状体（降低87-88%）中由左旋多巴形成受到抑制。仅在30mg/kg的OR-462剂量下，纹状体中的高香草酸（HVA）降低。氯吉兰（8mg/kg和32mg/kg腹腔注射）使下丘脑和纹状体中3,4-二羟基苯乙酸（DOPAC）的形成降低61-91%。当联合给药时，OR-462和氯吉兰使下丘脑多巴胺水平升高3.2-4.6倍，但纹状体多巴胺仅升高1.3-1.9倍。3-OMD和DOPAC的形成仍然受到抑制，甚至脑HVA水平降低了51-97%。6-OHDA处理使纹状体和下丘脑多巴胺降低50%，去甲肾上腺素降低75%。与完整动物相比，在这些动物中左旋多巴/卡比多巴使脑左旋多巴增加2.4-4倍，3-OMD增加1.2-1.7倍，但多巴胺的合成和代谢以及COMT和MAO抑制剂的作用没有显著变化。左旋多巴/卡比多巴治疗显著降低了血清中的催乳素和促甲状腺激素水平，但没有其他治疗改变这种作用。
