Abstract

Ischemic stroke, a leading cause of neurological morbidity, is characterized by extensive neuronal injury and a robust inflammatory response. Erbin, a scaffold protein involved in multiple cellular signaling pathways, regulates neuroinflammation and may confer neuroprotection against ischemia-reperfusion (I/R) injury. A mouse model of middle cerebral artery occlusion (MCAO) was utilized to evaluate the neuroprotective role of Erbin. Male mice were allocated into groups receiving either a lentiviral (LV) control vector or LV-mediated Erbin overexpression, followed by I/R injury induction. Neurological function, infarct volume, and expression levels of inflammatory cytokines and mitogen-activated protein kinase (MAPK) signaling proteins were analyzed. Overexpression of Erbin via LV transduction significantly reduced cerebral infarct volume and mitigated neurological impairments post-I/R injury. Furthermore, Erbin overexpression suppressed the phosphorylation of p38 and extracellular signal-regulated kinase (ERK) in HT22 neuronal cells, indicating attenuation of MAPK pathway activation. Notably, Erbin overexpression modulated the inflammatory response elicited by I/R injury, leading to a reduction in pro-inflammatory cytokine levels.Significance Statement This study reveals that Erbin overexpression protects against cerebral ischemia-reperfusion injury by inhibiting MAPK pathway activation, specifically by inhibiting the phosphorylation of ERK and p38. Erbin mitigates infarct volume, improves neurological function, and suppresses inflammatory cytokines in both in vivo and in vitro models. These findings highlight Erbin as a potential therapeutic target for ischemic stroke, offering a novel strategy to combat neuroinflammation and neuronal damage.