Tripathy D, Chakraborty J, Mohanakumar K P
Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology , Kolkata , India.
Free Radic Res. 2015;49(9):1129-39. doi: 10.3109/10715762.2015.1045505. Epub 2015 Jun 4.
Sporadic Parkinson's disease (PD) is a geriatric disorder with unknown etiology, specifically affecting the nigrostriatal dopaminergic (DA-ergic) pathway of the brain. Amongst several contributing factors, nitric oxide (NO•) is considered to inflict injury to DA-ergic neurons, and to influence PD progression. Supportive evidence for this comes from animal models of PD, where inhibitors of NO• synthase (NOS) are found to protect against DA-ergic neuronal death, and NOS-deficient mice are found to be resistant to PD-producing neurotoxins. Presence of nitrated proteins and upregulated levels of NOS in human postmortem PD brain samples have rendered further support to this contention. While NO• from neuronal NOS contributes to neurodegeneration in PD, NO• produced by inducible NOS from proliferating microglia as inflammatory responses to neuronal insults are suggested to mediate the disease progression. Another view that NO• in small doses serves as a neuroprotective agent in the brain is also discussed, in light of experimental evidence available in vitro and in vivo. This view is based on the argument that NO• could form harmless nitrites and nitrates on reaction with endogenously produced reactive oxygen species (ROS) within the cells. This review essentially discusses the possibilities of considering NO• as a secondary response of DA-ergic cell death, while oxidative stress is the primary cause. Once neurons undergo death processes following uncontrolled oxidative insult, the resulting gliosis-mediated NO• accelerates the events as a secondary mediator. Since the time of initiation of DA-ergic cell death cannot be predicted, NO• could be an ideal molecular target to halt the disease progression.
散发性帕金森病（PD）是一种病因不明的老年疾病，特别影响大脑的黑质纹状体多巴胺能（DA能）通路。在多种促成因素中，一氧化氮（NO•）被认为会对DA能神经元造成损伤，并影响PD的进展。对此的支持证据来自PD动物模型，在该模型中发现NO•合酶（NOS）抑制剂可防止DA能神经元死亡，且发现NOS缺陷小鼠对产生PD的神经毒素具有抗性。人类帕金森病死后脑样本中存在硝化蛋白质和NOS水平上调，进一步支持了这一观点。虽然神经元型NOS产生的NO•会导致PD中的神经退行性变，但增殖性小胶质细胞作为对神经元损伤的炎症反应，由诱导型NOS产生的NO•被认为介导了疾病进展。根据体外和体内的实验证据，还讨论了另一种观点，即小剂量的NO•在大脑中作为神经保护剂。这一观点基于这样的论点，即NO•与细胞内内源性产生的活性氧（ROS）反应时可形成无害的亚硝酸盐和硝酸盐。本综述主要讨论了将NO•视为DA能细胞死亡的次要反应的可能性，而氧化应激是主要原因。一旦神经元在不受控制的氧化损伤后经历死亡过程，由此产生的胶质增生介导的NO•作为次要介质加速这些事件。由于无法预测DA能细胞死亡的起始时间，NO•可能是阻止疾病进展的理想分子靶点。
