Pioglitazone ameliorates motor impairments and spinal cord pathologies in a mouse model of neuromyelitis optica spectrum disorders

Abstract

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system inflammatory demyelinating diseases characterised by recurrent optic neuritis and myelitis. Binding of pathogenic aquaporin-4 autoantibodies (AQP4-IgG) to AQP4 on astrocytes triggers lesion development that is driven by astrocyte-microglia interaction. Pioglitazone exerts neuroprotective effects through suppressing microglia activation in various models of CNS insults. Here we examined whether pioglitazone ameliorates motor impairments and pathologies in mice which received human AQP4-IgG. Methods: Mice with disrupted blood-brain barrier received passive transfer of purified IgG from AQP4-IgGseropositive NMOSD patients. Pioglitazone was administered by oral gavage. Motor impairments were assessed by beam walking test. Spinal cord pathologies were examined by immunofluorescence and ELISA. Results: Oral administration of pioglitazone ameliorated the motor impairments induced by AQP4-IgG. Pioglitazone profoundly reduced AQP4 and astrocyte loss, demyelination and axonal loss in the spinal cord of mice which received AQP4-IgG. The protective effects of pioglitazone were associated with suppression of neuroinflammation, with decrease in microglia activation and reduction in levels of proinflammatory cytokines including interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha). Conclusion: Our findings support that microglia activation plays an important role in the pathophysiologies of NMOSD and highlight the potential of pioglitazone as a therapeutic agent in NMOSD acute attacks.