SA4503 plays a protective role in post-resuscitation injury by reducing apoptosis caused by mitochondrial dysfunction and endoplasmic reticulum stress through the activation of sigma-1 receptor

Objective: Cardiac arrest followed by resuscitation can induce brain injury, and currently, there are no effective treatments for brain damage after cardiopulmonary resuscitation (CPR), necessitating the exploration of additional therapeutic strategies and prevention approaches. This study aimed to investigate the mechanism of action by which SA4503 activates the Sigma-1 receptor (Sig-1R) to protect against ischemic brain injury in both in vitro and in vivo models. The goal of this study was to provide theoretical support for SA4503 as a potential therapeutic agent and promote clinical intervention research for post-resuscitation brain injury following CPR. Material and Methods: This study explored the mechanism underlying the ability of Sig-1R activation to mitigate brain injury following cardiac arrest and resuscitation in rats through both in vivo and in vitro models. The methods used include enzyme-linked immunosorbent assay, magnetic resonance imaging, Western blot analysis, and flow cytometry. Results: The in vivo results demonstrated that the Sig-1R agonist SA4503 significantly attenuated neurological deficits in rats subjected to CPR. In vitro mechanistic investigations revealed that SA4503 potently reversed Sig-1R protein downregulation, reduced apoptosis, ameliorated mitochondrial dysfunction, and reduced endoplasmic reticulum (ER) stress in the oxygen-glucose deprivation/reperfusion (OGD/R) group. Conclusion: This study further confirms that Sig-1R activation confers protective effects against brain injury following cardiac arrest and resuscitation, as well as against OGD/R-induced injury in HT22 cells. The underlying mechanism involves the mitigation of apoptosis driven by mitochondrial dysfunction and ER stress.