Abstract
Introduction: Mitochondria-targeted S-nitrosothiol MitoSNO offers protection against ischemia-reperfusion injury by attenuating the reverse electron transport of mitochondrial complex I during reperfusion. This study aimed to assess whether administration of MitoSNO after ROSC improves neurological and survival outcomes following cardiac arrest (CA). Methods: Adult male rats were subjected to 10 minute of asphyxial CA followed by mechanical ventilation and manual CPR. After successful CPR, animals were assigned to one of two experimental groups: receiving respiration buffer as a vehicle or MitoSNO (100 ng per dose). Based on our preliminary study, two doses of each drug were intravenously injected via femoral vein: immediately after ROSC and at 60 minutes post-ROSC. The survival time and neurological function score (NFS) were recorded for up to 72 h. Surgery, CPR, drug injections, echocardiography, and immunohistochemistry were performed in a blind manner. Results: MitoSNO significantly improved NFS and survival rate ( Fig A ). Echocardiography revealed that MitoSNO improved left ventricular ejection fraction 2 h post-ROSC compared to the vehicle. In another set of experiments, relative cerebral blood flow (rCBF) compared to baseline was invasively monitored at 2 h post-CA using a laser speckle imaging. The imaging showed CA caused a reduction in rCBF 2 h post-CA in the vehicle group, which was markedly improved by MitoSNO ( Fig B ). Western blotting assay showed, in brain 2 h post-CA, MitoSNO significantly mitigated protein levels of 3-NT, a marker for nitrogen free radical-modified proteins, and cleaved Caspase-3, an indicator of programmed cell death. Immunohistochemistry revealed that MitoSNO suppressed neuronal degeneration in vulnerable brain regions of surviving animals. Conclusions: Our study demonstrated that MitoSNO inhibited the production of oxidative stress in the brain and improved neurological and survival outcomes following CA in rats.
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