Silencing of Abcc8 or inhibition of newly upregulated Sur1-Trpm4 reduce inflammation and disease progression in experimental autoimmune encephalomyelitis. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Makar, Tapas; Gerzanich, Volodymyr; Nimmagadda, Vamshi; Jain, Rupal; Lam, Kristal; Mubariz, Fahad; Trisler, David; Ivanova, Svetlana; Woo, Seung; Kwon, Min; Bryan, Joseph; Bever, Christopher; Simard, J.
• Is Part Of: Journal of neuroinflammation. Volume 12:Issue 1(2015)
• Page Start: 1
• Page End: 13
• Publication Date: 2015-12
• Subjects: Multiple sclerosis -- Experimental autoimmune encephalomyelitis -- Sur1 -- Trpm4 -- Sur1-Trpm4 channel -- Abcc8 -- Glibenclamide -- Astrocyte -- Inflammation -- Demyelination and neuroprotection; Central nervous system -- Diseases -- Periodicals; Inflammation -- Periodicals; 616.8
• DOI: 10.1186/s12974-015-0432-3
• Languages: English
• ISSNs: 1742-2094

Abstract

Abstract Background In experimental autoimmune encephalomyelitis (EAE), deletion of transient receptor potential melastatin 4 (Trpm4 ) and administration of glibenclamide were found to ameliorate disease progression, prompting speculation that glibenclamide acts by directly inhibiting Trpm4. We hypothesized that in EAE, Trpm4 upregulation is accompanied by upregulation of sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which are highly sensitive to glibenclamide, and that Sur1-Trpm4 channels are required for EAE progression. Methods EAE was induced in wild-type (WT) andAbcc8 −/− mice using myelin oligodendrocyte glycoprotein 35–55 (MOG35–55 ). Lumbar spinal cords were examined by immunohistochemistry, immuno-Förster resonance energy transfer (immunoFRET), and co-immunoprecipitation for Sur1-Trpm4. WT/EAE mice were administered with the Sur1 inhibitor, glibenclamide, beginning on post-induction day 10. Mice were evaluated for clinical function, inflammatory cells and cytokines, axonal preservation, and white matter damage. Results Sur1-Trpm4 channels were upregulated in EAE, predominantly in astrocytes. The clinical course and severity of EAE were significantly ameliorated in glibenclamide-treated WT/EAE and inAbcc8 −/−/EAE mice. At 30 days, the lumbar spinal cords of glibenclamide-treated WT/EAE andAbcc8 −/−/EAE mice showed significantly fewer invading immune cells, including leukocytes (CD45), T cells (CD3), B cells (CD20) and macrophages/microglia (CD11b), and fewer cells expressing pro-inflammatory cytokines (TNF-α, IFN-γ, IL-17). In both glibenclamide-treated WT/EAE andAbcc8 −/−/EAE mice, the reduced inflammatory burden correlated with better preservation of myelin, better preservation of axons, and more numerous mature and precursor oligodendrocytes. Conclusions Sur-Trpm4 channels are newly upregulated in EAE and may represent a novel target for disease-modifying therapy in multiple sclerosis.