Nitric oxide synthase and neuronal vulnerability in Parkinson's disease
Nitric oxide synthase and neuronal vulnerability in Parkinson's disease
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DOI：
10.1016/0306-4522(95)00578-1
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发表时间：
1996-05-01
期刊：
影响因子：
3.3
通讯作者：
Hirsch, EC
中科院分区：
文献类型：
--
作者：
Hunot, S;Boissiere, F;Hirsch, EC
帕金森病的特征是中脑多巴胺能神经元的丧失。尽管这种神经元损失的机制仍不清楚，但氧化应激很可能参与导致神经细胞死亡的级联事件。由于一氧化氮可能参与自由基的产生，因此我们使用免疫组织化学和组织化学分析了四名特发性帕金森病患者和三名匹配对照受试者中脑中一氧化氮的产生系统。使用针对一氧化氮合酶（参与一氧化氮合成的酶）的诱导亚型的特异性抗体，我们发现证据表明该亚型仅存在于表现出活化巨噬细胞形态特征的神经胶质细胞中。然而，用抗一氧化氮合酶神经元亚型的抗体进行的免疫组织化学分析显示了神经元的核周和突起，但没有神经胶质细胞染色。使用一氧化氮合酶的NADPH-心肌黄酶活性通过组织酶学研究含有一氧化氮合酶的细胞的数量。组织化学显示（i）帕金森病中以神经元丢失为特征的多巴胺能细胞群中 NADPH 心肌黄酶阳性神经胶质细胞密度显着增加，以及（ii）帕金森病中色素 NADPH 心肌黄酶阴性神经元的神经元丢失是色素 NADPH 心肌黄酶阳性神经元的两倍。这些数据表明，神经胶质细胞在神经元中产生过量的一氧化氮具有潜在的有害作用。帕金森病可能对多巴胺能神经元亚群具有神经毒性，尤其是那些不表达 NADPH 心肌黄酶活性的神经元。然而，不能排除帕金森病患者黑质中表达一氧化氮合酶的神经胶质细胞的存在代表多巴胺能神经元损失的结果。
Parkinson's disease is characterized by a loss of dopaminergic neurons in the mesencephalon. Although the mechanism of this neuronal loss is still unknown, oxidative stress is very likely involved in the cascade of events leading to nerve cell death. Since nitric oxide could be involved in the production of free radicals, we analysed, using immunohistochemistry and histochemistry, the production systems of nitric oxide in the mesencephalon of four patients with idiopathic Parkinson's disease and three matched control subjects. Using specific antibodies directed against the inducible isoform of nitric oxide synthase (the enzyme involved in the synthesis of nitric oxide), we found evidence to suggest that this isoform was present solely in glial cells displaying the morphological characteristics of activated macrophages. Immunohistochemical analysis performed with antibodies against the neuronal isoform of nitric oxide synthase, however, revealed perikarya and processes of neurons but no glial cell staining. The number of nitric oxide synthase-containing cells was investigated by histoenzymology, using the NADPH-diaphorase activity of nitric oxide synthase. Histochemistry revealed (i) a significant increase in NADPH-diaphorase-positive glial cell density in the dopaminergic cell groups characterized by neuronal loss in Parkinson's disease ana(ii) a neuronal loss in Parkinson's disease that was two-fold greater for pigmented NADPH-diaphorase-negative neurons than for pigmented NADPH-diaphorase-positive neurons.These data suggest a potentially deleterious role of glial cells producing excessive levels of nitric oxide in Parkinson's disease, which may be neurotoxic for a subpopulation of dopaminergic neurons, especially those not expressing NADPH-diaphorase activity. However, it cannot be excluded that the presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represents a consequence of dopaminergic neuronal loss.