Pioglitazone ameliorates sepsis-associated encephalopathy through SIRT1 signaling pathway

•Hyperinflammatory response plays a crucial role in the pathogenesis of multiple organ damage and neurological deficits associated with sepsis.•SIRT1 may be considered as an emerging regulator in sepsis-induced organ damage. It can deacetylate various downstream targets involved in sepsis pathophysiology.•The neuroprotective effect of pioglitazone (PPARγ agonist) in sepsis associated encephalopathy is mediated by attenuation of LPS-induced cerebral oxidative stress, microglia activation, HMGB hyperacetylation, NLRP3 activation and neuronal apoptosis.•The neuroprotective effects mediated by pioglitazone is SIRT1-dependent as blocking SIRT1 pathway by EX-527 lessen most of pioglitazone neuroprotective effects. Sepsis is a severe immune response to an infection. It is associated with multiple organ dysfunction syndrome (MODs) along with systemic and neuronal inflammatory response. This study focused on the acute neurologic dysfunction associated with sepsis by exploring the role of PPARγ/SIRT1 pathway against sepsis. We studied the role of this axis in ameliorating sepsis-associated encephalopathy (SAE) and its linked neurobehavioral disorders by using pioglitazone (PIO). This PPARγ agonist showed neuroprotective actions in neuroinflammatory disorders. Sepsis was induced in mice by LPS (10 mg/kg). Survival rate and MODs were assessed. Furthermore, behavioral deficits, cerebral oxidative, inflammatory, and apoptotic markers, and the cerebral expression level of SIRT1 were determined. In this study, we observed that PIO attenuated sepsis-induced cerebral injury. PIO significantly enhanced survival rate, attenuated MODs, and systemic inflammatory response in septic mice. PIO also promoted cerebral SIRT1 expression and reduced cerebral activation of microglia, oxidative stress, HMGB, iNOS, NLRP3 and caspase-3 along with an obvious improvement in behavioral deficits and cerebral pathological damage induced by LPS. Most of the neuroprotective effects of PIO were abolished by EX-527, a SIRT1 inhibitor. These results highlight that the neuroprotective effect of PIO in SAE is mainly SIRT1-dependent.