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

Vollständiger Abstract

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ABSTRACT 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.