Terazosin Alleviates Apoptosis and Neuroinflammation in Cerebral Ischemia-reperfusion Injury via Activating the PI3K/AKT/mTOR Signaling Pathway.

Ischemic stroke remains a major cause of disability and death worldwide, and effective neuroprotective treatments are urgently needed. This study investigated whether Terazosin (TZ), a clinically approved drug with neuroprotective potential, ameliorated Cerebral Ischemia-Reperfusion Injury (CIRI) and explored the underlying mechanisms. This study integrated network pharmacology analysis with in vivo experimental validation to investigate the neuroprotective effects of TZ against CIRI. Neurological deficits, infarct volume, and brain edema were evaluated in mice. TTC, TUNEL, and Nissl staining, as well as Western blotting, immunofluorescence staining, and quantitative real-time PCR (qPCR), were used to evaluate cell apoptosis, inflammation, and the activity of the PI3K/AKT/mTOR signaling pathway. Potential targets associated with TZ and CIRI were obtained from public databases, followed by GO and KEGG enrichment analyses of the overlapping targets. Statistical analyses were performed using GraphPad Prism 10.1, and P < 0.05 was considered statistically significant. TZ treatment significantly reduced cerebral infarct volume and improved neurological function in a mouse MCAO/R model. It attenuated neuronal apoptosis, as evidenced by increased Bcl-2 expression and decreased Bax expression, and suppressed neuroinflammation, as indicated by reduced levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and decreased microglial activation. Bioinformatics analysis identified 140 overlapping targets between TZ and CIRI, with PIK3CA, MTOR, and several other genes emerging as key hub genes. KEGG enrichment analysis revealed significant enrichment of the PI3K/AKT signaling pathway. Further mechanistic investigations revealed that TZ activated the PI3K/AKT/mTOR signaling pathway. Importantly, the neuroprotective effects of TZ were abolished by the PI3K inhibitor LY294002, supporting an essential role of this pathway in mediating the protective effects of TZ against CIRI. These findings indicate that TZ may protect against CIRI by suppressing apoptosis and neuroinflammation through activation of the PI3K/AKT/mTOR signaling pathway, thereby providing preclinical evidence for its potential repurposing as a treatment for ischemic stroke. In summary, this study demonstrates that TZ exerts neuroprotective effects against CIRI by activating the PI3K/AKT/mTOR signaling pathway. These results provide a preclinical basis for repurposing TZ as a treatment for ischemic stroke and highlight the PI3K/AKT/mTOR axis as a potential neuroprotective target.