Department of Neurology, Third Clinical Hospital, China Three Gorges University, 60 Qiaohu 1st Road, 443002 Yichang, China.
J Mol Neurosci. 2013 Jan;49(1):89-95. doi: 10.1007/s12031-012-9897-z. Epub 2012 Oct 5.
Overproduction of nitric oxide (NO) plays an important role in glutamate-induced excitotoxicity. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor. The aim of this study is to explore whether ADMA antagonizes the excitotoxicity of glutamate to neuronal cells and the underlying molecular mechanisms. In this work, we investigated the effects of ADMA on glutamate-induced toxicity in neuronal cells by studying PC12 cells, a clonal rat pheochromocytoma cell line. We show that ADMA obviously protects PC12 cells against glutamate-induced cytotoxicity and apoptosis. We also found that ADMA treatment results in prevention of glutamate-induced mitochondrial membrane potential loss and caspase-3 activation. Moreover, ADMA prevents glutamate-caused down-regulation of bcl-2 protein expression. These results indicate that ADMA protects against glutamate-induced apoptosis and excitotoxicity and the underlying mechanism may be involved in preservation of mitochondrial function by up-regulating the expression of bcl-2. Our study suggests a promising future of ADMA-based therapies for neuropathologies associated with an excess of NO.
一氧化氮（NO）的过度产生在谷氨酸诱导的兴奋性毒性中起着重要作用。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂。本研究旨在探讨 ADMA 是否拮抗谷氨酸对神经元细胞的兴奋性毒性及其潜在的分子机制。在这项工作中，我们通过研究 PC12 细胞（一种克隆大鼠嗜铬细胞瘤细胞系）来研究 ADMA 对谷氨酸诱导的毒性的影响。我们发现 ADMA 明显保护 PC12 细胞免受谷氨酸诱导的细胞毒性和细胞凋亡。我们还发现 ADMA 处理可防止谷氨酸诱导的线粒体膜电位丧失和 caspase-3 激活。此外，ADMA 可防止谷氨酸引起的 bcl-2 蛋白表达下调。这些结果表明，ADMA 可防止谷氨酸诱导的细胞凋亡和兴奋性毒性，其潜在机制可能涉及通过上调 bcl-2 的表达来维持线粒体功能。我们的研究表明，基于 ADMA 的治疗方法有望用于治疗与过量 NO 相关的神经病理学。
