title: Endothelin receptor A antagonism reduces the extent of diffuse axonal injury in a rodent model of traumatic brain injury.
abstract: OBJECTIVE
  While endothelin-1 and its receptors have traditionally been associated with mediating vasoreactivity, we have recently shown that the vast majority of endothelin receptor A expression following traumatic brain injury is localized within the neuron. While it has been suggested that endothelin receptor A plays a role in influencing neuronal integrity, the significance of neuronally expressed endothelin receptor A remains unclear. One report suggests that endothelin-1 signaling mediates diffuse axonal injury. Therefore, this work sought to determine whether treatment with BQ-123, a selective endothelin receptor A antagonist, diminishes the extent of diffuse axonal injury following trauma.
  
  
  METHODS
  A total of 12 male Sprague-Dawley rats (350-400 g) were used in this study. Two groups (n = 6 per group) were generated as follows: sham operation and traumatic brain injury+1·0 mg/kg BQ-123 delivered intravenously 30 minutes prior to the injury. Trauma was induced using a weight acceleration impact device. Animals were terminated 24 or 48 hours after trauma, and a series of six coronal sections through the entire anterior-posterior extent of the corpus callosum were selected from each brain for quantification of diffuse axonal injury by beta-amyloid precursor protein immunostaining.
  
  
  RESULTS
  Our data indicated that animals treated with BQ-123 30 minutes prior to trauma showed a significant reduction in diffuse axonal injury in corpus callosum at both 24 and 48 hours post-injury.
  
  
  CONCLUSIONS
  The results show that endothelin receptor A antagonism reduced the extent of diffuse axonal injury, demonstrating a potential influence of the endothelin system on the intra-axonal cascade of molecular events underlying diffuse axonal injury.
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Kallakuri
authors.forename: Mihir
authors.initials: M
authors.lastname: Bagchi
authors.forename: Steven
authors.initials: S
authors.lastname: Schafer
authors.forename: Christian W
authors.initials: CW
authors.lastname: Kreipke
authors.forename: José A
authors.initials: JA
authors.lastname: Rafols
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001369:Axons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020833:Diffuse Axonal Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D018696:Neuroprotective Agents; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)