Pioglitazone blocks play behavior impairments in a rat model of autism induced by prenatal LPS exposure via IL-6 pathway

Abstract

Autism is characterized by social deficits, communication abnormalities, and repetitive behaviors. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by gram-negative bacteria, induces autistic-like behaviors. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected pioglitazone as the postnatal treatment to block or ease the impairments induced by LPS because although it was designed as an anti-diabetic drug (insulin effect), it also exerts anti-inflammatory effects. Concomitant with other pharmacological and behavioral therapies, pioglitazone has already shown interesting beneficial effect in reversing some behavioral impairment in a case study with some autistic children. Juvenile offspring were daily treated with pioglitazone and one of the main behaviors related to autism were studied: play behavior. Biomarkers linked to autism and/or pioglitazone were also studied: IL-6, TNF-alpha, and MCP-1. Prenatal LPS exposure induced social deficits (social interactions, pinning, and darts) in juvenile rat offspring, as well as elevated plasma IL-6 levels. Daily postnatal pioglitazone treatment blocked both behavioral and IL-6 disturbances. Thus, pioglitazone appears to be a relevant candidate for the treatment of autism. The present findings may contribute to a better understanding and treatment of autism and associated diseases.