title: Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury.
abstract: Both glibenclamide and riluzole reduce necrosis and improve outcome in rat models of spinal cord injury (SCI). In SCI, gene suppression experiments show that newly upregulated sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channels in microvascular endothelial cells are responsible for "persistent sodium currents" that cause capillary fragmentation and "progressive hemorrhagic necrosis". Glibenclamide is a potent blocker of Sur1-regulated NC(Ca-ATP) channels (IC(50), 6-48 nM). Riluzole is a pleotropic drug that blocks "persistent sodium currents" in neurons, but in SCI, its molecular mechanism of action is uncertain. We hypothesized that riluzole might block the putative pore-forming subunits of Sur1-regulated NC(Ca-ATP) channels, Trpm4. In patch clamp experiments, riluzole blocked Sur1-regulated NC(Ca-ATP) channels in endothelial cells and heterologously expressed Trpm4 (IC(50), 31 μM). Using a rat model of cervical SCI associated with high mortality, we compared the effects of glibenclamide and riluzole administered beginning at 3h and continuing for 7 days after impact. During the acute phase, both drugs reduced capillary fragmentation and progressive hemorrhagic necrosis, and both prevented death. At 6 weeks, modified (unilateral) Basso, Beattie, Bresnahan locomotor scores were similar, but measures of complex function (grip strength, rearing, accelerating rotarod) and tissue sparing were significantly better with glibenclamide than with riluzole. We conclude that both drugs act similarly, glibenclamide on the regulatory subunit, and riluzole on the putative pore-forming subunit of the Sur1-regulated NC(Ca-ATP) channel. Differences in specificity, dose-limiting potency, or in spectrum of action may account for the apparent superiority of glibenclamide over riluzole in this model of severe SCI.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA. msimard@smail.umaryland.edu
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
authors.forename: Orest
authors.initials: O
authors.lastname: Tsymbalyuk
authors.forename: Kaspar
authors.initials: K
authors.lastname: Keledjian
authors.forename: Alexander
authors.initials: A
authors.lastname: Ivanov
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ivanova
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D019556:COS Cells; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects; D002452:Cell Count; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000235:genetics; D018737:Hand Strength / Q000502:physiology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D051381:Rats; D019782:Riluzole / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D050053:TRPM Cation Channels / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D061207:Calcium Ionophores; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000001:Calcimycin; D019782:Riluzole; D005905:Glyburide; D002118:Calcium