Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University, Hangzhou, China ; Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194, Japan.
Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194, Japan.
Oxid Med Cell Longev. 2013;2013:367206. doi: 10.1155/2013/367206. Epub 2013 Dec 24.
Oxidative stress is crucially involved in the pathogenesis of neurological diseases such as stroke and degenerative diseases. We previously demonstrated that platelet-derived growth factors (PDGFs) protected neurons from H2O2-induced oxidative stress and indicated the involvement of PI3K-Akt and MAP kinases as an underlying mechanism. Ca(2+) overload has been shown to mediate the neurotoxic effects of oxidative stress and excitotoxicity. We examined the effects of PDGFs on H2O2-induced Ca(2+) overload in primary cultured neurons to further clarify their neuroprotective mechanism. H2O2-induced Ca(2+) overload in neurons in a dose-dependent manner, while pretreating neurons with PDGF-BB for 24 hours largely suppressed it. In a comparative study, the suppressive effects of PDGF-BB were more potent than those of PDGF-AA. We then evaluated calpain activation, which was induced by Ca(2+) overload and mediated both apoptotic and nonapoptotic cell death. H2O2-induced calpain activation in neurons in a dose-dependent manner. Pretreatment of PDGF-BB completely blocked H2O2-induced calpain activation. To the best of our knowledge, the present study is the first to demonstrate the mechanism underlying the neuroprotective effects of PDGF against oxidative stress via the suppression of Ca(2+) overload and inactivation of calpain and suggests that PDGF-BB may be a potential therapeutic target of neurological diseases.
氧化应激在中风和退行性疾病等神经疾病的发病机制中起着至关重要的作用。我们之前的研究表明，血小板衍生生长因子（PDGFs）可保护神经元免受 H2O2 诱导的氧化应激，并表明 PI3K-Akt 和 MAP 激酶的参与是其潜在机制。已经证明钙超载介导氧化应激和兴奋毒性的神经毒性作用。我们研究了 PDGFs 对原代培养神经元中 H2O2 诱导的钙超载的影响，以进一步阐明其神经保护机制。H2O2 以剂量依赖性方式诱导神经元中的钙超载，而用 PDGF-BB 预处理神经元 24 小时则大大抑制了它。在一项比较研究中，PDGF-BB 的抑制作用比 PDGF-AA 更强。然后，我们评估了钙蛋白酶的激活，钙蛋白酶的激活是由钙超载诱导的，介导凋亡和非凋亡细胞死亡。H2O2 以剂量依赖性方式诱导神经元中的钙蛋白酶激活。PDGF-BB 的预处理完全阻断了 H2O2 诱导的钙蛋白酶激活。据我们所知，本研究首次证明了 PDGF 通过抑制钙超载和失活钙蛋白酶来对抗氧化应激的神经保护作用的机制，并表明 PDGF-BB 可能是神经疾病的潜在治疗靶点。
