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.