Reynolds Christian A, Schafer Steven, Pirooz Ryan, Marinica Alex, Chbib Ali, Bedford Christopher, Fronczak Michael, Rafols José A, Kuhn Donald, Kreipke Christian W
Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Neurol Res. 2011 Mar;33(2):197-200. doi: 10.1179/016164111X12881719352499.
Previously we have reported that endothelin receptor A and B antagonists elicit differential effects on cerebral blood flow and cellular damage. In summary, endothelin receptor A antagonists restore microcirculation and diminish cellular damage after injury, while endothelin receptor B antagonists had no effect on either parameter. However, what is not known is the effect of either antagonist on behavioral outcome. Therefore, this work was designed to test the effects of endothelin receptor A and B antagonism on behavioral outcome following traumatic brain injury (TBI).
A total of 48 male Sprague-Dawley rats (400-450 g) were used in this study. Four groups (n = 12 per group) were generated as follows: sham operation, trauma+vehicle (0·9% saline), trauma+40 nmol BQ-123 (a selective endothelin receptor A antagonist) and trauma +20 nmol BQ-788 (a selective endothelin receptor B antagonist). All treatments were delivered via intracerebroventricular injection. Trauma was induced using a weight acceleration impact device. Twenty-four hours post-injection animals were tested for 21 days on a radial arm maze task to determine cognitive outcome.
Our data indicated that endothelin receptor A antagonism significantly reduced the extent of behavioral deficits following TBI while endothelin receptor B and vehicle injection had no effect.
The results suggest that endothelin receptor A, but not endothelin receptor B, antagonism improves behavioral outcome following TBI. Furthermore, these data provide a functional correlate to previously published findings in our laboratory showing that endothelin receptor A antagonism improves both blood flow and cellular outcome following TBI. In a broader sense, this work demonstrates that hypoperfusion following TBI likely contributes to poor outcome following head injury.
此前我们报道过内皮素A和B受体拮抗剂对脑血流量和细胞损伤有不同影响。简而言之，内皮素A受体拮抗剂可恢复微循环并减轻损伤后的细胞损伤，而内皮素B受体拮抗剂对这两个参数均无影响。然而，尚不清楚这两种拮抗剂对行为结果有何影响。因此，本研究旨在测试内皮素A和B受体拮抗作用对创伤性脑损伤（TBI）后行为结果的影响。
本研究共使用48只雄性Sprague-Dawley大鼠（400 - 450克）。分为四组（每组n = 12），如下：假手术组、创伤+载体（0.9%生理盐水）组、创伤+40 nmol BQ - 123（一种选择性内皮素A受体拮抗剂）组和创伤+20 nmol BQ - 788（一种选择性内皮素B受体拮抗剂）组。所有处理均通过脑室内注射给药。使用重量加速撞击装置诱导创伤。注射后24小时，对动物进行为期21天的放射状臂迷宫任务测试，以确定认知结果。
我们的数据表明，内皮素A受体拮抗作用显著降低了TBI后行为缺陷的程度，而内皮素B受体拮抗剂和载体注射均无影响。
结果表明，内皮素A受体而非内皮素B受体的拮抗作用可改善TBI后的行为结果。此外，这些数据为我们实验室之前发表的研究结果提供了功能相关性，表明内皮素A受体拮抗作用可改善TBI后的血流量和细胞结果。从更广泛的意义上讲，这项研究表明TBI后的灌注不足可能导致头部损伤后的不良结果。
