SWAP70 alleviates brain damage and neuroinflammation induced by cerebral ischemia-reperfusion by inhibiting autophagy.

Abstract

Cerebral ischemia-reperfusion (CIR) injury is a leading cause of neurological disability and is characterized by oxidative stress, inflammation, and excessive autophagy, all of which converge to promote neuronal injury and death. Autophagy plays a dual role in this setting by helping to maintain cellular homeostasis under stress, yet it can drive neurodegeneration when overactivated. Switch-associated protein 70 (SWAP70), a Rho GTPase exchange factor that regulates cytoskeletal dynamics and immune responses, has been implicated in neural differentiation and inflammatory regulation; however, its role in CIR injury remains unclear. In this study, using middle cerebral artery occlusion/reperfusion (MCAO/R) mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated SH-SY5Y cells, we found that SWAP70 expression was significantly reduced after ischemic injury. Notably, SWAP70 overexpression improved neurological function and reduced infarct size, neuronal damage, and cytokine release in MCAO/R mice. Consistently, in OGD/R-treated SH-SY5Y cells, SWAP70 overexpression restored cell viability, decreased LDH release, and suppressed the expression of autophagy-related proteins. Importantly, rapamycin treatment reversed the protective effects of SWAP70, confirming that SWAP70 alleviates brain injury by inhibiting excessive autophagy. Furthermore, SWAP70 overexpression suppressed NF-κB pathway activation. In conclusion, SWAP70 mitigates CIR injury by inhibiting excessive autophagy and dampening neuroinflammation, thereby providing a potential therapeutic target for ischemic stroke.