Endothelin receptor A antagonism reduces the extent of diffuse axonal injury in a rodent model of traumatic brain injury.

Abstract

OBJECTIVES:

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.

CONCLUSION:

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: Christian A Reynolds, Srinivasu Kallakuri, Mihir Bagchi, Steven Schafer, Christian W Kreipke, José A Rafols
• Journal: Neurological research (Neurol Res) Vol. 33 Issue 2 Pg. 192-6 (Mar 2011) ISSN: 1743-1328 [Electronic] England
• PMID: 21801594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antihypertensive Agents
• Endothelin A Receptor Antagonists
• Endothelin-1
• Neuroprotective Agents
• Peptides, Cyclic
• Receptor, Endothelin A
• cyclo(Trp-Asp-Pro-Val-Leu)

Topics

• Animals
• Antihypertensive Agents (administration & dosage)
• Axons (drug effects, pathology, physiology)
• Brain Injuries (drug therapy, metabolism, pathology)
• Diffuse Axonal Injury (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Endothelin A Receptor Antagonists
• Endothelin-1 (physiology)
• Injections, Intravenous
• Male
• Neuroprotective Agents (pharmacology)
• Peptides, Cyclic (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A (physiology)
• Signal Transduction (drug effects, physiology)
• Treatment Outcome