Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury

Phillip G. Popovich, Stanley Lemeshow, John C. Gensel, C. Amy Tovar

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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 24h post-injury using a colorimetric assay. Acute recovery (24h) 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 24-48h 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.

Original languageEnglish
Pages (from-to)615-622
Number of pages8
JournalExperimental Neurology
Volume233
Issue number2
DOIs
StatePublished - Feb 2012

Bibliographical note

Funding Information:
Thanks to Drs. J. Marc Simard, Orest Tsymaluk and Volodymyr Gerzanich for the thoughtful and invaluable discussions throughout these experiments. Thank you also to Drs. Dana McTigue, Michele Basso, Lyn Jakeman, John Buford, Sandra Kostyk and the technical staff and trainees of the Center for Brain and Spinal Cord Repair for the discussions related to manuscript selection and experimental design. Sponsored by NIH -NINDS contract HHSN271200800040C to P.G.P.

Keywords

  • Cervical spinal cord injury
  • Glibenclamide
  • Hemorrhage
  • Injury models
  • Secondary injury
  • Sulfonylurea receptor

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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