Memantine and pioglitazone ameliorate motor impairments and complement-independent cord pathologies in mice received aquaporin-4 autoantibodies from neuromyelitis optica spectrum disorder (NMOSD) patients

Abstract

Background: NMOSD are predominantly autoimmune astrocytopathy characterized by recurrent attacks of CNS inflammation. Binding of aquaporin-4 autoantibodies (AQP4-IgG) to astrocytic AQP4 triggers neuroinflammation. We reported AQP4-IgG induced motor impairments associated with complement-independent astrocytic injury, glutamate transporter (EAAT2) loss, microglial/macrophage activation, demyelination and axonal injury in mice with breached blood-brain-barrier (BBB); suggesting a role of glutamate excitotoxicity and microglial/macrophage activation in NMOSD pathophysiologies. Objective: To examine whether memantine (NMDA receptor antagonist) and pioglitazone (peroxisome proliferatoractivated receptor-γ agonist) can attenuate motor impairments and pathologies in mice received AQP4-IgG. Methods: After breaching BBB with bacterial proteins, mice received daily intraperitoneal injections of IgG purified from AQP4-IgG-seropositive NMOSD patients [IgG(AQP4+)] or healthy individuals as control for 8 days. IgG(AQP4+) mice received daily oral gavage of vehicle, or 60 mg/kg memantine or 80 mg/kg pioglitazone. Motor functions were assessed by beam walking test. Spinal cords were collected for immunofluorescence analysis. Results: Vehicle-treated IgG(AQP4+) mice required longer time with more paw slips to walk across narrow beams than sham. Memantine and pioglitazone significantly reduced the time and number of paw slips of IgG(AQP4+) mice compared with vehicle (p<0.01), suggesting motor function improvement. Neither memantine nor pioglitazone reduced aquaporin-4 loss in spinal cord of IgG(AQP4+) mice compared with vehicle. Importantly, memantine and pioglitazone significantly reduced glial fibrillary acidic protein loss (p<0.05), microglial/ macrophage activation (p<0.001), demyelination (p<0.001) and axonal loss (p<0.05) in IgG(AQP4+) mice compared with vehicle, suggesting an improvement of IgG(AQP4+)-induced complement-independent pathologies. Conclusion: Memantine and pioglitazone have therapeutic potentials for ameliorating severity of NMOSD attack.