Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Policlinico G. Martino, Viale Gazzi, 98124, Messina, Italy.
Amino Acids. 2020 Feb;52(2):171-179. doi: 10.1007/s00726-019-02759-6. Epub 2019 Jul 10.
Agmatine, a metabolite generated by arginine decarboxylation, has been reported as neuromodulator and neuroactive substance. Several findings suggest that agmatine displays neuroprotective effects in several models of neurodegenerative disorders, such as Parkinson's disease (PD). It has been hypothesized that biogenic amines may be involved in neuroprotection by scavenging oxygen radicals, thus preventing the generation of oxidative stress. Mitochondrial dysfunction, that leads to a reduction of oxygen consumption, followed by activation of prolyl hydroxylase and decrease of hypoxia-inducible factor 1 alpha (HIF-1α) levels, has been demonstrated to play a role in PD pathogenesis. Using rotenone-treated differentiated SH-SY5Y cells as the in vitro PD model, we here investigated the molecular mechanisms underlying agmatine neuroprotective effects. Our results showed that the preliminary addition of agmatine induces HIF-1α activation, and prevents the rotenone-induced production of free radical species, and the activation of apoptotic pathways by inhibiting mitochondrial membrane potential decrease and caspase 3 as well as cytochrome c increase. Notably, these effects are mediated by HIF-1α, as indicated by experiments using a HIF-1α inhibitor. The present findings suggest that the treatment with agmatine is able to counteract the neuronal cell injury evoked by mitochondrial toxins.
胍丁胺是精氨酸脱羧酶生成的代谢产物，已被报道为神经调质和神经活性物质。一些研究结果表明，胍丁胺在几种神经退行性疾病模型中显示出神经保护作用，如帕金森病（PD）。有人假设生物胺可能通过清除氧自由基来参与神经保护，从而防止氧化应激的产生。已经证明线粒体功能障碍导致耗氧量减少，随后脯氨酰羟化酶激活和缺氧诱导因子 1α（HIF-1α）水平降低，在 PD 发病机制中起作用。我们使用鱼藤酮处理的分化 SH-SY5Y 细胞作为体外 PD 模型，在此研究了胍丁胺神经保护作用的分子机制。我们的结果表明，胍丁胺的初步添加诱导 HIF-1α 激活，并通过抑制线粒体膜电位降低和 caspase 3 以及细胞色素 c 增加来防止鱼藤酮诱导的自由基产生和凋亡途径的激活。值得注意的是，这些作用是由 HIF-1α介导的，这是通过使用 HIF-1α 抑制剂的实验表明的。这些发现表明，胍丁胺的治疗能够抵抗线粒体毒素引起的神经元细胞损伤。
