Greenamyre J T, Eller R V, Zhang Z, Ovadia A, Kurlan R, Gash D M
Department of Neurology, University of Rochester Medical Center, NY 14642.
Ann Neurol. 1994 Jun;35(6):655-61. doi: 10.1002/ana.410350605.
Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N-methyl-D-aspartate receptor ion channel. In normal rats and monoamine-depleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK-801. When monoamine-depleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5-40 mg/kg, orally) caused a dose-dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100-200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa-carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa-carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa-carbidopa was substantially better than levodopa-carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N-methyl-D-aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.
纹状体多巴胺能神经支配的丧失导致从丘脑底核到苍白球内侧段和黑质网状部（基底神经节的输出核团）的谷氨酸能通路过度活跃。先前的研究表明，局部阻断苍白球内侧段或黑质网状部的谷氨酸受体可显著抑制帕金森病体征。我们现在研究了谷氨酸受体拮抗剂全身给药在帕金森病啮齿动物和灵长类动物模型中是否具有抗帕金森病作用。盐酸瑞马西胺是一种抗惊厥、具有神经保护作用的化合物，对N-甲基-D-天冬氨酸受体离子通道具有拮抗活性。与MK-801不同，在正常大鼠和单胺耗竭的大鼠中，盐酸瑞马西胺不会引起运动亢进。当用阈下剂量的左旋多巴甲酯治疗单胺耗竭的大鼠时，盐酸瑞马西胺（5-40mg/kg，口服）可引起运动活性的剂量依赖性增加。此外，盐酸瑞马西胺（10mg/kg，口服）增强了所测试的每个阈上剂量的左旋多巴甲酯（100-200mg/kg，腹腔注射）的作用。对帕金森病恒河猴口服给予溶剂加溶剂、溶剂加左旋多巴-卡比多巴以及盐酸瑞马西胺（5mg/kg）加左旋多巴-卡比多巴进行测试。对录像带进行盲法临床评分显示，盐酸瑞马西胺加左旋多巴-卡比多巴的治疗效果明显优于左旋多巴-卡比多巴加溶剂或溶剂加溶剂。盐酸瑞马西胺的作用至少持续5小时。我们得出结论，某些N-甲基-D-天冬氨酸受体拮抗剂具有抗帕金森病作用且副作用可能性低。盐酸瑞马西胺在帕金森病患者中的临床试验可能是有必要的。
