Novel Treatment For Traumatic Brain Injury

Objective: We hypothesized that targeting ETrA could mitigate the deleterious effects of TBI. Background Traumatic brain injury results in multiple pathologies, including significant reduction in cerebral blood flow. Our laboratory have shown that endothelin-1 plays a major role in the induction of hypoperfusion. Furthermore, we demonstrated that the endothelin receptor A (ETrA) is upregulated as early as 4 hours post TBI and maintains upregulation up to 48 hours, thus temporally corresponding with the state of hypoperfusion. Design/Methods: Using a rodent model of diffuse traumatic brain injury (acceleration impact in Sprague-Dawley rats), we tested the effects of IV administration of a selective ETrA antagonist, Clazosentan administered at various times post TBI on CBF (as measured up to 48 hours post injury using arterial spin labeling MRI, n=6 per group) and behavioral outcome (measured up to 20 days post injury using a radial arm maze-spatial learning task, n=12-15 per group) following injury. Results: Our results indicate that when Clazosentan is administered at 30 minutes, 2 hours, or 4 hours after TBI there is a marked decrease in the extent of TBI-induced hypoperfusion. However, administration at 12 hours post-TBI resulted in variable effects (i.e., some animals improved, some worsened, and some remained the same). The most effective paradigm was a dual-administration approach in which drug was given at 2 and 24 hours post-TBI. Behavioral results recapitulated the blood flow results, showing that there was a trend towards improved behavioral outcome when Clazosentan was administered at 2 hours, however a significant improvement was seen when given at 2 and 24 hours. Conclusions: These results suggest that selective ETrA antagonism may be effective in mitigating the deleterious effects of TBI. Furthermore, it appears that our results help to define the “window of opportunity of drug delivery”. Supported by: NIH-NS064976(CK,PI), VARR&D-RX000224(CK, PI), and American Academy of Neurology(MK). Disclosure: Dr. Kaufman has nothing to disclose. Dr. Tiesma has nothing to disclose. Dr. Kreipke has received research support from Veterans Administration and National Institute of Health.