Roles of metformin and pioglitazone in regulating neurotoxic astrocyte activation in EAE mice

Neuro-inflammation is a vital mediator involved in the pathology of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Neurotoxic A1 reactive astrocytes associate with neuro-inflammatory reactivity in MS/EAE. Although Metformin and Pioglitazone, two antidiabetic drugs, inhibit inflammation, the regulation mechanisms underlying A1 astrocytes in MS remain unclear. Herein, we show that Metformin and/or Pioglitazone downregulate inflammatory response, the activation of A1 astrocytes and the AKT/mTOR/STAT3 signaling pathway in primary mouse astrocytes treated with IL-17. In EAE mice, Metformin and/or Pioglitazone decreased significantly inflammation and demyelination and ameliorated the pathological process of disease. Overall, these findings uncover that Metformin and/or Pioglitazone suppress the inflammatory response in A1 astrocytes and alleviate the pathogenesis of EAE mice in vitro and in vivo . Targeting the cytotoxicity of A1 astrocytes may be a promising strategy for treating demyelinating diseases.