Moussaoui S, Obinu M C, Daniel N, Reibaud M, Blanchard V, Imperato A
Aventis Pharma, CNS Program, Centre de Recherche de Vitry-Alfortville (Building CRV8), 13, quai Jules Guesde, Vitry sur Seine Cedex, 94403, France.
Exp Neurol. 2000 Dec;166(2):235-45. doi: 10.1006/exnr.2000.7516.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), via its major metabolite 1-methyl-4-phenylpyridinium (MPP(+)), produces in primates including humans clinical, biochemical, and neuropathological changes similar to those which occur in idiopathic Parkinson's disease. Ebselen is an antioxidant drug with glutathione peroxidase-like activity and a proven neuroprotective action in stroke patients. Here we show that Ebselen, when administered before, during, and after MPTP injections, prevents both neuronal loss and clinical symptoms in a primate MPTP model of Parkinson's disease. Ebselen also prevents peroxide radical overproduction induced by serum withdrawal in cultured PC12 cells and hydroxyl radical generation induced by the mitochondrial toxin, MPP(+), in vivo in rat brain. Moreover, Ebselen inhibits MPP(+)-induced toxicity in PC12 cells, without interacting with the dopamine uptake system. Our results demonstrate that compounds which prevent mitochondrial dysfunction and free radical production may be useful as preventive treatment of Parkinson's disease.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）通过其主要代谢产物1-甲基-4-苯基吡啶鎓（MPP⁺），在包括人类在内的灵长类动物中引发临床、生化和神经病理学变化，这些变化与特发性帕金森病中出现的变化相似。依布硒仑是一种具有谷胱甘肽过氧化物酶样活性的抗氧化药物，在中风患者中具有已证实的神经保护作用。在此我们表明，在MPTP注射之前、期间和之后给予依布硒仑，可预防帕金森病灵长类MPTP模型中的神经元损失和临床症状。依布硒仑还可预防培养的PC12细胞中血清撤除诱导的过氧化物自由基过量产生以及大鼠脑内线粒体毒素MPP⁺在体内诱导的羟基自由基生成。此外，依布硒仑在不与多巴胺摄取系统相互作用的情况下，抑制PC12细胞中MPP⁺诱导的毒性。我们的结果表明，预防线粒体功能障碍和自由基产生的化合物可能作为帕金森病的预防性治疗药物有用。
