Pioglitazone Modulates Microglia M1/M2 Polarization Through PPAR-γ Pathway and Exerts Neuroprotective Effects in Experimental Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH), a subtype of hemorrhagic stroke primarily resulting from the rupture of intracranial aneurysms, remains a significant contributor to disability and mortality, notwithstanding advancements in treatment. This study investigates the neuroprotective effects of pioglitazone in SAH, focusing on the PPAR-γ pathway and its potential role in mitigating early brain injury (EBI) following SAH. Neuroprotective efficacy was assessed through neurobehavioral assessment, brain water content analysis, TUNEL, immunofluorescence, western blotting, and inflammatory factor assay. Results indicate that pioglitazone treatment effectively mitigated brain edema, reduced neuronal death, and enhanced short-term neurobehavioral function in SAH-afflicted rats. Furthermore, pioglitazone demonstrated sustained improvements in long-term neurobehavioral function and decreased neuronal loss post-SAH. Mechanistically, SAH induced the polarization of microglia towards the M1 phenotype and the release of pro-inflammatory cytokines. Conversely, pioglitazone treatment predominantly shifted microglia polarization towards the M2 phenotype, eliciting a notable release of anti-inflammatory cytokines. Notably, the positive effects of pioglitazone were nullified by the PPAR-γ inhibitor T0070907. In conclusion, our findings suggest that pioglitazone may alleviate neuroinflammation by modulating microglia M1/M2 polarization through the PPAR-γ pathway, thereby conferring neuroprotection against SAH injury and positing itself as a potential therapeutic agent for SAH treatment.