中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (3): 398-399.doi: 10.4103/1673-5374.179039

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

为脑卒中神经保护铺路:抑制AMPK/ nNOS通路

  

  • 收稿日期:2016-02-14 出版日期:2016-03-15 发布日期:2016-03-15

Inhibition of the AMPK/nNOS pathway for neuroprotection in stroke

Mushfiquddin Khan, Inderjit Singh   

  1. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
  • Received:2016-02-14 Online:2016-03-15 Published:2016-03-15
  • Contact: Mushfiquddin Khan, Ph.D., khanm@musc.edu.

摘要:

在美国,脑卒中在所有会导致死亡的疾病中排名第四,是造成长期残疾的主要原因。除了组织纤溶酶原激活剂溶栓以外(它仅在较短治疗窗(3-4小时)之间有效),目前还没有一个有效的神经保护或功能恢复的治疗策略,这主要是因为我们对脑卒中信号机制的了解有限。脑卒中后,由于一氧化氮合成酶的异常活动,一氧化氮代谢会失调;在神经元中,是由过氧化亚硝酸盐产物而不是亚硝基(谷胱甘肽)来控制代谢。尽管过氧化亚硝酸盐在脑卒中中有着主要因果作用,但因为我们对一氧化氮合成酶调控/信号和过氧亚硝酸盐改性的靶向目标机制理解有限,因此神经元过亚硝酸盐-或一氧化氮合成酶的靶向治疗就可以利用。为了阐明谷胱甘肽和过亚硝酸盐在脑卒中中的作用,以及它们在缺血再灌注后与过亚硝酸盐的潜在联系,研究需要阐明一氧化氮合成酶蛋白磷酸化/脱磷酸化和巯基亚硝基/脱亚硝基,以及和/或硝基酪氨酸及其调节酶之间复杂的相互作用。毫无疑问,这些反应确定了一氧化氮合成酶的作用和过量过氧化亚硝酸盐和亚硝基在脑卒中中的潜在作用。和nNOS 经一氧化氮合成酶的特异性抑制剂治疗的KO小鼠和野生型小鼠均显示出缺血再灌注损伤程度降低,以及神经系统功能改善,这一结果支持了研究一氧化氮合成酶介导损伤机制的必要性,并可以制定一氧化氮合成酶针对脑卒中治疗的神经保护及功能恢复策略。一氧化氮合成酶的活动由多种机制介导,包括S-亚硝基(NO /谷胱甘肽),AMP激酶和过氧亚硝酸盐调控。因此,这篇观点文章的重点是研究依赖性一氧化氮合成酶在脑卒中中的两种机制,并改善其在短暂性脑缺血再灌注损伤动物模型中使用谷胱甘肽新型巯基亚硝基化的机制。也许,在这个领域的发现可以用于药物开发,可以扩大或开辟脑卒中新的治疗窗口并提供新的机遇。

Abstract:

Stroke ranks fourth among all causes of death and is the major cause of long-term disability in the United States. Other than thrombolysis by tissue plasminogen activator (tPA), which offers only a short window of treatment (~3-4 hours), an effective neuroprotective or functional recovery therapy is not available mainly because of limited understanding of the signaling mechanisms of stroke disease. After stroke, the nitric oxide (NO) metabolome is derailed due to aberrant activities of nitric oxide synthases (NOS). In neurons, peroxynitrite production comes to dominate the metabolome rather than S-Nitrosoglutathione (GSNO). In spite of peroxynitrite’s major, causal role in stroke, neuronal peroxynitrite- or nNOS-targeted therapy does not exist due to limited mechanistic understanding of nNOS regulation/signaling and peroxynitrite-modified targets. In order to tease out the roles of GSNO and peroxynitrite in stroke and their potential links to outcomes after IR, research needs to elucidate the complex interplay between phosphorylation/dephosphoryaltion and S-nitrosylation/denitrosylation and/or nitrotyrosination of nNOS and its regulatory enzymes. Undoubtedly, these reactions determine the role of nNOS and the potential effects of excess peroxynitrite and GSNO on outcomes following stroke. Both wild type mice treated with nNOS specific inhibitors and nNOS KO mice show reduced levels of IR injury and improved neurological functions following IR, supporting the need to investigate the nNOS-mediated injury mechanisms and to develop an nNOS targeted stroke therapy for neuroprotection and recovery of functions. nNOS activity is regulated by several mechanisms/mediators, including S-nitrosylation (NO/GSNO), AMP kinase, and peroxynitrite. Therefore, the focus of this perspective is to examine both mechanisms of the NOS-dependent stroke disease and its amelioration by novel S-nitrosylation mechanisms using GSNO in an animal model of transient cerebral ischemia reperfusion (IR). Perhaps discoveries in this realm could offer new opportunities for drug development that could widen or open new therapeutic windows for stroke.