Wu R M, Mohanakumar K P, Murphy D L, Chiueh C C
Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health Clinical Center 10/3D-41, Bethesda, Maryland 20892.
Ann N Y Acad Sci. 1994 Nov 17;738:214-21. doi: 10.1111/j.1749-6632.1994.tb21806.x.
The current research has demonstrated that MPP+ can induce lipid peroxidation in the nigrostriatal system of rat in vivo. Antioxidant agent U-78517F and .OH scavenger DMSO may protect against MPP+ toxicity through the inhibition of .OH radical-mediated oxidative injury in the substantia nigra. These findings indicate that the cytotoxic hydroxyl radical generated from dopamine oxidation in the iron-rich basal ganglia may contribute to the mechanism underlying the selective A9 melanized nigral degeneration in MPTP-Parkinsonism and possibly in idiopathic Parkinson's disease. In addition, the present studies also clearly demonstrate that deprenyl can substantially protect dopaminergic neurons against MPP+ toxicity in the substantia nigra zona compacta in vivo. The neuroprotective effect provided by deprenyl may not be the consequence of its inhibition of MAO-B activity or prevention of the uptake of MPP+ by dopaminergic neurons. A unique antioxidant property of deprenyl by suppressing .OH formation and associated oxidative injury induced by MPP+ may contribute to the apparent neuroprotective action. In perspective, this putative antioxidant effect of deprenyl may provide another mechanism to its overt neuroprotective effects against oxygen radical-mediated oxidative injury in some neurotoxic chemicals, such as 6-OHDA and DSP-4, and probably in Alzheimer's disease and senescent changes. Finally, based on the present data, a possible neuroprotective therapeutic window of deprenyl in the treatment of early Parkinson's disease has been proposed. It is suggested that deprenyl should be introduced as early as possible in de novo Parkinsonian patients to achieve its full neuroprotective effect on nigral degeneration. Moreover, a combination of early detection of individuals at risk of developing Parkinson's disease and early intervention of deprenyl and/or other centrally active antioxidants to these patients may provide a new preventive therapeutic strategy in the future, in addition to the current conventional levodopa treatment of Parkinson's disease.
目前的研究表明，1-甲基-4-苯基吡啶离子（MPP+）可在大鼠体内黑质纹状体系统中诱导脂质过氧化。抗氧化剂U-78517F和羟基自由基（·OH）清除剂二甲基亚砜（DMSO）可能通过抑制黑质中·OH自由基介导的氧化损伤来保护细胞免受MPP+毒性的影响。这些发现表明，在富含铁的基底神经节中，多巴胺氧化产生的细胞毒性羟基自由基可能参与了MPTP诱导的帕金森综合征以及可能的特发性帕金森病中选择性A9黑质致密部黑素化神经元变性的机制。此外，本研究还清楚地表明，司来吉兰在体内可显著保护黑质致密部的多巴胺能神经元免受MPP+毒性的影响。司来吉兰提供的神经保护作用可能不是其抑制单胺氧化酶B（MAO-B）活性或防止多巴胺能神经元摄取MPP+的结果。司来吉兰通过抑制MPP+诱导的·OH形成及相关氧化损伤而具有独特的抗氧化特性，这可能是其明显的神经保护作用的原因。从这个角度来看，司来吉兰这种假定的抗氧化作用可能为其对某些神经毒性化学物质（如6-羟基多巴胺和N,N-二甲基-4-苯基硫代乙酰胺）以及可能在阿尔茨海默病和衰老变化中氧自由基介导的氧化损伤的明显神经保护作用提供另一种机制。最后，基于目前的数据，提出了司来吉兰在早期帕金森病治疗中可能的神经保护治疗窗。建议在初发帕金森病患者中尽早使用司来吉兰，以使其对黑质变性发挥充分的神经保护作用。此外，除了目前对帕金森病的传统左旋多巴治疗外，对有患帕金森病风险个体的早期检测以及对这些患者尽早使用司来吉兰和/或其他中枢活性抗氧化剂进行干预，可能在未来提供一种新的预防性治疗策略。
