Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity
Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity
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DOI：
10.1073/pnas.93.10.4565
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发表时间：
1996-05-14
影响因子：
11.1
通讯作者：
Dawson, TM
中科院分区：
文献类型：
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作者：
Przedborski, S;JacksonLewis, V;Dawson, TM
1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 会导致黑质纹状体多巴胺能通路损伤，类似于帕金森病 (PD) 中观察到的情况。为了研究 NO 自由基在 MPTP 诱导的神经毒性中的作用，我们将 MPTP 注射到小鼠体内，其中一氧化氮合酶 (NOS) 被 7-硝基吲唑 (7-NI) 以时间和剂量依赖性方式抑制。 7-NI 显着保护注射 MPTP 的小鼠免受黑质纹状体多巴胺能通路严重损伤的影响，包括纹状体多巴胺含量减少、黑质酪氨酸羟化酶阳性神经元数量减少以及大量银染退化黑质神经元。注射7-NI的小鼠对MPTP的抵抗不是由于纹状体药代动力学或MPTP活性代谢物1-甲基-4-苯基吡啶鎓离子(MPP(+))含量的改变。为了专门研究神经元一氧化氮合酶 (nNOS) 的作用，将 MPTP 给予缺乏 nNOS 基因的突变小鼠。与野生型同窝小鼠相比，突变小鼠对 MPTP 诱导的神经毒性具有明显更强的抵抗力。这些结果表明，神经源性 NO 部分介导 MPTP 诱导的神经毒性。MPTP 模型与 PD 之间的相似性提出了 NO 可能在 PD 病因学中发挥重要作用的可能性。
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP(+)), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity, The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.