Abstract
The aim of this study is to investigate the relation between CaMKII S-nitrosylation and its activation, as well as the underlying mechanism, after global cerebral ischemia-reperfusion. The rat model of cerebral ischemia-reperfusion was established by four-vessel occlusion of 15 min and reperfusion of different times. nNOS inhibitor 7-nitroindazole (7-NI), exogenous nitric oxide donor GSNO (nitrosoglutathione), or N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 were administered before ischemia. The expressions of S-nitrosylation and phosphorylation of CaMKII and nNOS were detected by biotin switch assay, immunoblotting, and immunohistochemical staining after cerebral ischemia-reperfusion. The survival of hippocampal CA1 pyramidal cells after administration of the three drugs was examined by cresyl violet staining. Following cerebral ischemia-reperfusion, the S-nitrosylation of CaMKII was increased, accompanied by a decrease of phosphorylation, suggesting a decrease of activity (p<0.05). Meanwhile, the phosphorylation and S-nitrosylation of nNOS were notably decreased at the same time point (p<0.05). The administration of 7-NI, GSNO, and MK-801 increased the S-nitrosylation and phosphorylation of nNOS, leading to the attenuation of increased S-nitrosylation and decreased autophosphorylation of CaMKII after cerebral ischemia-reperfusion (p<0.05). Administration of MK-801, GSNO, and 7-NI significantly decreased the neuronal damage in rat hippocampal CA1 caused by cerebral ischemia-reperfusion (p<0.05). After cerebral ischemia-reperfusion, the decrease of autophosphorylation of CaMKII regulated by its S-nitrosylation may be due to the denitrosylation of nNOS and subsequent NO production. Increasing the phosphorylation of CaMKII by nNOS inhibitor, exogenous NO donor or NMDA receptor antagonist exerted neuroprotective effects against cerebral ischemia-reperfusion injury.
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