Urushitani M, Shimohama S
Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyoku, Japan.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2001 Jun;2(2):71-81. doi: 10.1080/146608201316949415.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuronal death. The cause of ALS is unclear, but accumulating evidence, such as the insufficient clearance of glutamate through the glutamate transporter, and the specific distribution of Ca2+-permeable AMPA receptors in spinal motor neurons, indicates that glutamate-induced neurotoxicity is involved in its pathogenesis. Interestingly, nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor (EDRF), was found to be a pivotal inducer of glutamate-induced neuronal death. NO is generated by nitric oxide synthase (NOS), of which there are three subtypes: neuronal NOS expressed mainly in neurons, inducible NOS in astroglia, and endothelial NOS in vessels. NO-related toxicity is caused by peroxynitrite, formed by the reaction of NO with superoxide anions, resulting in the nitration of tyrosine residues in neurofilaments, irreversible inhibition of the mitochondrial respiratory chain, and inhibition of the glutamate transporter. Clinically, the axonal spheroids of motor neurons are reported to be immunoreactive to anti-nitrotyrosine antibody, and there are elevated levels of the metabolites of NO in the cerebrospinal fluid of ALS patients. Since physiologically normal motor neurons express limited amounts of neuronal NOS, the source of NO is considered to be non-motor neurons expressing neuronal NOS, astroglia expressing inducible NOS, or motor neurons themselves inducing neuronal NOS. Conversely, neurons containing neuronal NOS are known to be resistant to toxic stimuli, which raises the possibility that such neurons are protected by NO. Several mechanisms have been reported to mediate the NO-related neuroprotection, including cyclic guanosine 3',5'-monophosphate (cyclic GMP), a downstream product of NO generation. This review summarizes previous studies on NO, focusing on its dual functions of neurotoxicity or neuroprotection, and discusses the putative roles of NO in relation to the pathogenesis of ALS.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征为选择性运动神经元死亡。ALS的病因尚不清楚，但越来越多的证据，如通过谷氨酸转运体对谷氨酸的清除不足，以及Ca2+通透性AMPA受体在脊髓运动神经元中的特定分布，表明谷氨酸诱导的神经毒性参与了其发病机制。有趣的是，一氧化氮（NO）已被鉴定为内皮衍生舒张因子（EDRF），它被发现是谷氨酸诱导的神经元死亡的关键诱导物。NO由一氧化氮合酶（NOS）产生，NOS有三种亚型：主要在神经元中表达的神经元型NOS、星形胶质细胞中的诱导型NOS和血管中的内皮型NOS。与NO相关的毒性是由过氧亚硝酸盐引起的，过氧亚硝酸盐是由NO与超氧阴离子反应形成的，导致神经丝中酪氨酸残基的硝化、线粒体呼吸链的不可逆抑制以及谷氨酸转运体的抑制。临床上，据报道运动神经元的轴突球对抗硝基酪氨酸抗体具有免疫反应性，并且ALS患者脑脊液中NO代谢产物水平升高。由于生理上正常的运动神经元表达有限量的神经元型NOS，NO的来源被认为是表达神经元型NOS的非运动神经元、表达诱导型NOS的星形胶质细胞或自身诱导神经元型NOS的运动神经元。相反，已知含有神经元型NOS的神经元对毒性刺激具有抗性，这增加了此类神经元受到NO保护的可能性。据报道，有几种机制介导与NO相关的神经保护作用，包括NO生成的下游产物环鸟苷酸3',5'-单磷酸（环鸟苷酸）。本综述总结了先前关于NO的研究，重点关注其神经毒性或神经保护的双重功能，并讨论了NO在ALS发病机制中的假定作用。
