title: Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury.
abstract: These experiments were completed as part of an NIH-NINDS contract entitled "Facilities of Research Excellence - Spinal Cord Injury (FORE-SCI) - Replication". Our goal was to replicate pre-clinical data from Simard et al. (2007) showing that glibenclamide, an FDA approved anti-diabetic drug that targets sulfonylurea receptor 1 (SUR1)-regulated Ca(2+) activated, [ATP](i)-sensitive nonspecific cation channels, attenuates secondary intraspinal hemorrhage and secondary neurodegeneration caused by hemicontusion injury in rat cervical spinal cord. In an initial replication attempt, the Infinite Horizons impactor was used to deliver a standard unilateral contusion injury near the spinal cord midline. Glibenclamide was administered continuously via osmotic pump beginning immediately post-SCI. The ability of glibenclamide to limit intraspinal hemorrhage was analyzed at 6, 12 and 24 h post-injury using a colorimetric assay. Acute recovery (24 h) of forelimb function was also assessed. Analysis of data from these initial studies revealed no difference between glibenclamide and vehicle-treated SCI rats. Later, it was determined that differences in primary trauma affect the efficacy of glibenclamide. Indeed, the magnitude and distribution of primary intraspinal hemorrhage was greater when the impact was directed to the dorsomedial region of the cervical hemicord (as in our initial replication experiment), as compared to the dorsolateral spinal cord (as in the Simard et al. experiment). In three subsequent experiments, injury was directed to the dorsolateral spinal cord. In each case, glibenclamide reduced post-traumatic hemorrhage 24-48 h post-injury. In the third experiment, we also assessed function and found that acute reduction of hemorrhage led to improved functional recovery. Thus, independent replication of the Simard et al. data was achieved. These data illustrate that the injury model and type of trauma can determine the efficacy of pre-clinical pharmacological treatments after SCI.
authors.affiliation: Center for Brain and Spinal Cord Repair and Department of Neuroscience, The Ohio State University College of Medicine, Columbus, OH, United States. phillip.popovich@osumc.edu
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
authors.forename: Stanley
authors.initials: S
authors.lastname: Lemeshow
authors.forename: John C
authors.initials: JC
authors.lastname: Gensel
authors.forename: C Amy
authors.initials: CA
authors.lastname: Tovar
mesh_terms: D000818:Animals; D002574:Cervical Vertebrae / Q000473:pathology; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005905:Glyburide / Q000627:therapeutic use*; D046748:Hematoma, Epidural, Spinal / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D009336:Necrosis; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D005905:Glyburide