Abstract
BackgroundNeuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG.MethodsPurified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA.ResultsOral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in the spinal cord.ConclusionsOur findings support that glutamate excitotoxicity and neuroinflammation play important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.
Highlights
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory demyelinating disorders of the central nervous system (CNS) clinically characterized by recurrent attacks of acute optic neuritis, transverse myelitis, and less frequently encephalitis
The majority of NMOSD patients are seropositive for aquaporin-4 immunoglobulin G autoantibodies (AQP4-IgG), which target the water channel aquaporin-4 (AQP4) [2, 3] that is highly expressed on the membrane of astrocytic foot processes [4]
We recently reported that passive transfer of human AQP4-IgG to mice with disrupted BBB led to complement-independent NMOSD-like spinal cord pathologies of AQP4 and astrocyte loss, excitatory amino acid transporter 2 (EAAT2) loss, microglia activation, neutrophil infiltration, demyelination, and axonal loss, which were associated with motor impairments [13]
Summary
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory demyelinating disorders of the central nervous system (CNS) clinically characterized by recurrent attacks of acute optic neuritis, transverse myelitis, and less frequently encephalitis. Complementindependent events likely contribute to the early development of NMOSD lesions These events include AQP4 loss from internalization and degradation of the antigenautoantibody complex [8], glutamate excitotoxicity from reduction of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) [9, 10], neuroinflammation due to release of proinflammatory cytokines and chemokines from astrocytes [11], and antibody-dependent cellmediated cytotoxicity (ADCC) which involves microglia/ macrophages and granulocytes [12]. Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG
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