Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis

Background: in multiple sclerosis (ms) and experimental autoimmune encephalomyelitis (eae),inflammation is perpetuated by both infiltrating leukocytes and astrocytes. recent work implicated sur1-trpm4 channels,expressed mostly by astrocytes,in murine eae. we tested the hypothesis that pharmacological inhibition of sur1 during the chronic phase of eae would be beneficial. methods: eae was induced in mice using myelin oligodendrocyte glycoprotein (mog) 35-55. glibenclamide (10 μg/day) was administered beginning 12 or 24 days later. the effects of treatment were determined by clinical scoring and tissue examination. drug within eae lesions was identified using bodipy-glibenclamide. the role of sur1-trpm4 in primary astrocytes was characterized using patch clamp and qpcr. demyelinating lesions from ms patients were studied by immunolabeling and immunofret. results: administering glibenclamide beginning 24 days after mog35-55 immunization,well after clinical symptoms had plateaued,improved clinical scores,reduced myelin loss,inflammation (cd45,cd20,cd3,p65),and reactive astrocytosis,improved macrophage phenotype (cd163),and decreased expression of tumor necrosis factor (tnf),b-cell activating factor (baff),chemokine (c-c motif) ligand 2 (ccl2) and nitric oxide synthase 2 (nos2) in lumbar spinal cord white matter. glibenclamide accumulated within eae lesions,and had no effect on leukocyte sequestration. in primary astrocyte cultures,activation by tnf plus ifnγ induced de novo expression of sur1-trpm4 channels and upregulated tnf,baff,ccl2,and nos2 mrna,with glibenclamide blockade of sur1-trpm4 reducing these mrna increases. in demyelinating lesions from ms patients,astrocytes co-expressed sur1-trpm4 and baff,ccl2,and nos2. conclusions: sur1-trpm4 may be a druggable target for disease modification in ms. © 2017 the author(s).