PPARγ-Dependent Pioglitazone Treatment Suppresses Neuroinflammation and Improves Cognition in Sepsis-Associated Encephalopathy in Mice.

OBJECTIVE: To assess whether pioglitazone (Pio) protects against sepsis-associated encephalopathy (SAE) and to probe underlying mechanisms. METHODS: Sepsis was induced in male C57BL/6 mice by caecal ligation and puncture (CLP). At 24 h post-CLP, mice received Pio and/or the PPAR-γ antagonist GW9662 and were followed for 14-day survival. Cognitive and affective behaviors were evaluated using a behavioral battery. Blood-brain barrier (BBB) permeability was assessed by Evans blue extravasation, and hippocampal inflammatory and apoptotic readouts were examined by ELISA, immunoblotting, and TUNEL staining. RESULTS: CLP reduced 14-day survival to 21.82%, whereas Pio increased survival to 46.15%; GW9662 abolished this benefit (19.36%). Pio improved behavior consistent with reduced anxiety-like behavior and better learning/memory. Mechanistically, Pio decreased Evans blue leakage and increased Claudin-5, suppressed TLR4/NF-κB-associated inflammation (lower TNF-α, IL-1β, and IL-6; higher IL-10), and reduced neuronal apoptosis; these effects were largely reversed by GW9662. CONCLUSION: Pioglitazone alleviates sepsis-induced brain dysfunction and improves survival in mice in a PPAR-γ-dependent manner.