Ebadi M, Srinivasan S K, Baxi M D
Department of Pharmacology, University of Nebraska College of Medicine, Omaha 68198-6260, USA.
Prog Neurobiol. 1996 Jan;48(1):1-19. doi: 10.1016/0301-0082(95)00029-1.
Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease.
帕金森病，也被称为纹状体多巴胺缺乏综合征，是一种中枢神经系统的退行性疾病，其特征为运动不能、肌肉僵硬、静止性震颤和姿势异常。在帕金森病早期，多巴胺受体数量似乎会出现代偿性增加，以适应多巴胺神经元的最初损失。随着疾病进展，多巴胺受体数量减少，这显然是由于纹状体神经元上多巴胺靶点的伴随性退化所致。帕金森病中多巴胺能神经元的丧失导致多巴胺代谢增强，增加了过氧化氢的形成，从而导致产生高度神经毒性的羟基自由基（OH·）。自由基的产生也可由6-羟基多巴胺或MPTP引起，它们会破坏纹状体多巴胺能神经元，在实验动物和人类中引发帕金森病。对帕金森病患者死后黑质的研究表明存在氧化应激和还原型谷胱甘肽耗竭；总铁水平高而铁蛋白水平降低；以及线粒体复合体I缺乏。旨在减轻氧化应激影响并为帕金森病中纹状体多巴胺能神经元提供神经保护的新方法包括用吗茚酮阻断多巴胺转运体、用马来酸二氢麦角碱阻断NMDA受体、通过给予脑源性神经营养因子提高神经元存活率、提供抗氧化剂如维生素E，或用司来吉兰抑制单胺氧化酶B（MAO-B）。在所有这些实验性治疗改进中，司来吉兰的使用最为成功，因为已表明司来吉兰可能具有类似神经营养因子的作用，可挽救纹状体神经元并延长帕金森病患者的生存期。
