Terazosin Attenuates Neuronal Pyroptosis by Regulating the Mitochondrial ROS/NLRP3 Inflammasome Axis Through Mitophagy in Cerebral Ischemia-Reperfusion Injury.

Cerebral ischemia-reperfusion injury (CI/RI) is a major cause of secondary neuronal damage following ischemic stroke. This study investigated whether terazosin (TZ) exerts neuroprotective effects by regulating mitophagy and the reactive oxygen species (ROS)/NOD-like receptor protein 3 (NLRP3) inflammasome axis. A mouse model of CI/RI was established and treated with TZ alone or in combination with the mitophagy inhibitor Mdivi-1 or the NLRP3 activator nigericin. Neurological function, infarct volume, histopathological changes in the hippocampal CA1 region, mitophagy (Mito-Tracker+LC3B+), and neuronal pyroptosis (NeuN+GSDMD-N+) were evaluated. In parallel, an oxygen-glucose deprivation/reperfusion (OGD/R) model was established in HT-22 cells to assess cell viability, cytotoxicity, mitochondrial membrane potential, ROS production, inflammatory cytokine release, and expression of autophagy- and pyroptosis-related proteins. The CI/RI exhibited was characterized by worsened neurological deficits, increased infarct volume, enhanced neuronal pyroptosis, and elevated interleukin-1β (IL-1β), IL-18, ROS, p62, and pyroptosis proteins, as well as prominent vacuolation and edema in the hippocampal CA1 region. These changes were accompanied by reduced mitophagy and decreased expression of LC3B II/I and Beclin-1. TZ treatment markedly ameliorated these abnormalities. Mechanistic analyses showed that TZ inhibited OGD/R-induced neuronal pyroptosis by promoting mitophagy, which reduced ROS accumulation and subsequently suppressed NLRP3 inflammasome activation. Importantly, blockade of mitophagy or activation of NLRP3 weakened the protective effects of TZ. Collectively, these findings indicate that TZ mitigates CI/RI-induced neuronal injury by enhancing mitophagy and inhibiting ROS/NLRP3-dependent pyroptosis.