Department of Histology and Neurobiology, Dokkyo Medical University School of Medicine, 880 Kita-Kobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.
Department of Basic Science, Educational and Research Center for Pharmacy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, Tokyo, 204-8588, Japan.
Nitric Oxide. 2018 Aug 1;78:41-50. doi: 10.1016/j.niox.2018.05.007. Epub 2018 May 22.
Neuronal nitric oxide synthase (nNOS) is involved in nigrostriatal dopaminergic (DA) neurodegeneration. However, little is known about the distribution patterns and functions of nNOS in slowly progressive DA neurodegeneration. Here we describe the spatiotemporal change in nNOS expression over the course of neurodegeneration and the effect of short- or long-term treatment with the nNOS inhibitor, 7-nitroindazole (7-NI), in zitter (zi/zi) rats. In the substantia nigra pars compacta (SNc), nNOS expression was significantly increased with progression of neurodegeneration. nNOS-immunoreactive (ir) cells were in the vicinity of tyrosine hydroxylase-ir (TH-ir) DA neurons, and some of these cells were also positive for calbindin. nNOS in the caudate-putamen (CPu) showed little difference during progression of neurodegeneration. However, immunoelectron microscopic analysis revealed that abundant TH-ir fibers in the CPu were degenerated due to compression by vacuoles that contained swollen neuronal and glial elements. Additionally, lipid peroxidation as a marker of membrane oxidation was significantly increased in zi/zi rats. Short-term 7-NI treatment attenuated the increase in lipid peroxidation and inhibited the vacuolation in the CPu. Moreover, long-term 7-NI treatment significantly protected TH-ir neurons in the SNc, and TH-ir fibers and DA contents in the CPu. These results show that nNOS exacerbates slowly progressive DA neurodegeneration, and the neuroprotective effects of 7-NI may result from suppression of membrane oxidation that causes abnormal membrane structures in zi/zi rats.
神经元型一氧化氮合酶（nNOS）参与黑质纹状体多巴胺能（DA）神经退行性变。然而，对于 nNOS 在缓慢进行性 DA 神经退行性变中的分布模式和功能知之甚少。在这里，我们描述了 nNOS 表达在神经退行性变过程中的时空变化，以及短期或长期使用 nNOS 抑制剂 7-硝基吲唑（7-NI）对颤搐（zi/zi）大鼠的影响。在黑质致密部（SNc）中，随着神经退行性变的进展，nNOS 表达显著增加。nNOS-免疫反应（ir）细胞靠近酪氨酸羟化酶-ir（TH-ir）DA 神经元，其中一些细胞也对钙结合蛋白呈阳性。在纹状体（CPu）中，nNOS 在神经退行性变进展过程中差异不大。然而，免疫电镜分析显示，CPu 中丰富的 TH-ir 纤维由于含有肿胀神经元和神经胶质成分的空泡的压迫而退化。此外，作为膜氧化标记的脂质过氧化显著增加。短期 7-NI 治疗可减轻脂质过氧化的增加，并抑制 CPu 中的空泡形成。此外，长期 7-NI 治疗可显著保护 SNc 中的 TH-ir 神经元以及 CPu 中的 TH-ir 纤维和 DA 含量。这些结果表明，nNOS 加重了缓慢进行性 DA 神经退行性变，7-NI 的神经保护作用可能源于抑制导致 zi/zi 大鼠异常膜结构的膜氧化。
