Neurodegenerative Diseases Research Centre, School of Biomedical Sciences, King's College, London, UK.
Brain Res. 2011 Aug 2;1404:21-30. doi: 10.1016/j.brainres.2011.05.063. Epub 2011 Jun 13.
Nitric oxide is linked with neurodegeneration in Parkinson's disease (PD) through the involvement of both inducible (iNOS) and neuronal nitric oxide synthase (nNOS). While non-selective NOS inhibitors are neuroprotective, the role of nNOS has not been determined using selective NOS inhibitors. The present study investigated the neuroprotective effect of selective iNOS and nNOS inhibitors on MPP(+)- and MG-132-induced cell death in cell lines with differing levels of nNOS expression. Inhibition of endogenously expressed nNOS by 7-NI and ARR17477 enhanced the toxicity of MPP(+) and MG-132 in N1E-115 cells, whereas in transfected SH-SY5Y cells overexpressing nNOS, ARR17477 and 7-NI protected against MPP(+)- and MG-132-induced cell death. In contrast, inhibition of iNOS by 1400W was ineffective in preventing MPP(+) and MG-132 toxicity in these cell lines. These results suggest a dual role for NOS in dopaminergic cell viability. nNOS is protective against toxic insult when produced endogenously. When nNOS is overexpressed, it becomes neurotoxic to cells suggesting that inhibition of nNOS may be a promising strategy to prevent cell death in PD.
一氧化氮通过诱导型（iNOS）和神经元型一氧化氮合酶（nNOS）的参与与帕金森病（PD）中的神经变性有关。虽然非选择性 NOS 抑制剂具有神经保护作用，但使用选择性 NOS 抑制剂尚未确定 nNOS 的作用。本研究调查了选择性 iNOS 和 nNOS 抑制剂对具有不同 nNOS 表达水平的细胞系中 MPP(+)和 MG-132 诱导的细胞死亡的神经保护作用。7-NI 和 ARR17477 抑制内源性表达的 nNOS 增强了 MPP(+)和 MG-132 在 N1E-115 细胞中的毒性，而在过表达 nNOS 的转染 SH-SY5Y 细胞中，ARR17477 和 7-NI 可抵抗 MPP(+)和 MG-132 诱导的细胞死亡。相比之下，1400W 抑制 iNOS 在这些细胞系中不能有效预防 MPP(+)和 MG-132 的毒性。这些结果表明 NOS 在多巴胺能细胞活力中具有双重作用。当内源性产生时，nNOS 具有保护作用。当 nNOS 过度表达时，它会对细胞产生神经毒性，这表明抑制 nNOS 可能是预防 PD 中细胞死亡的有前途的策略。
