title: Silencing of Abcc8 or inhibition of newly upregulated Sur1-Trpm4 reduce inflammation and disease progression in experimental autoimmune encephalomyelitis.
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) and Abcc8-/- 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 in Abcc8-/-/EAE mice. At 30 days, the lumbar spinal cords of glibenclamide-treated WT/EAE and Abcc8-/-/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 and Abcc8-/-/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.
authors.affiliation: Research Service and MS Center of Excellence, Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. Tmakar@som.umaryland.edu.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Tmakar@som.umaryland.edu.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Makar
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. vgerzanich@smail.umaryland.edu.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
authors.affiliation: Research Service and MS Center of Excellence, Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. VNimmagadda@som.umaryland.edu.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. VNimmagadda@som.umaryland.edu.
authors.forename: Vamshi K C
authors.initials: VK
authors.lastname: Nimmagadda
authors.affiliation: Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Rupal.Jain@som.umaryland.edu.
authors.forename: Rupal
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. knl2fv@virginia.edu.
authors.forename: Kristal
authors.initials: K
authors.lastname: Lam
authors.affiliation: Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. fahadm1@umbc.edu.
authors.forename: Fahad
authors.initials: F
authors.lastname: Mubariz
authors.affiliation: Research Service and MS Center of Excellence, Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. GTrisler@som.umaryland.edu.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. GTrisler@som.umaryland.edu.
authors.forename: David
authors.initials: D
authors.lastname: Trisler
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. sveta0652@yahoo.com.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ivanova
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. skwoo@smail.umaryland.edu.
authors.forename: Seung Kyoon
authors.initials: SK
authors.lastname: Woo
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. mskwon@smail.umaryland.edu.
authors.forename: Min Seong
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, WA, 98122, USA. jbryan@pnri.org.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bryan
authors.affiliation: Research Service and MS Center of Excellence, Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. Christopher.Bever@va.gov.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Christopher.Bever@va.gov.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Bever
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. msimard@smail.umaryland.edu.|Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. msimard@smail.umaryland.edu.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. msimard@smail.umaryland.edu.|Neurosurgical Service, Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. msimard@smail.umaryland.edu.|Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD, 21201-1595, USA. msimard@smail.umaryland.edu.
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D020868:Gene Silencing; D005905:Glyburide / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000187:drug effects; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010446:Peptide Fragments; D013116:Spinal Cord / Q000473:pathology; D064233:Sulfonylurea Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: C577508:Abcc8 protein, mouse; D007004:Hypoglycemic Agents; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D064233:Sulfonylurea Receptors; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D005905:Glyburide