Objective-s-: Pioglitazone -PGZ-, a peroxisome proliferator-activated receptor gamma -PPAR-γ- agonist, has significant neuroprotective effects and has been reported to regulate inflammatory processes. Materials and Methods: We evaluated the effects of PGZ on febrile seizure -FS- in rat pups. Three groups of male rat pups received intraperitoneal -IP- injections of PGZ -5, 10, and 20 mg/kg-. Lipopolysaccharide -LPS- and kainic acid -KA- were injected to induce FS. The rat pups behaviors were recorded and analyzed. Seizure latency, duration, and severity were recorded to evaluate the effect of PGZ on FS. Novel object recognition task -NORT- was used to evaluate the effect of PGZ on cognitive deficits induced by FS. At the end of the experimental protocol, molecular and histological tests were done. Results: PGZ significantly increased seizure latency and decreased seizure duration and median of seizure scores -P<0.05, P<0.01, and P<0.001- after induction of FS. Rat pups exposed to FS had memory deficits both in short-term and long-term memories in the NORT that were reversed by PGZtreatment -P<0.01 and P<0.001-. PGZ significantly reduced interleukin-1β, tumor necrosis factor-α, and inducible nitric oxide synthase concentration in the hippocampus -P<0.05 and P<0.01-. In addition, PGZ decreased the number of degenerating and TUNEL positive neurons in CA1, CA3, and DG subfields of the hippocampus -P<0.05, P<0.01 and P<0.001-. Conclusion: The present results indicated that PGZ had anticonvulsant, anti-inflammatory, and antiapoptotic effects with ameliorative effects on cognitive deficits induced by FS in rat pups.

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