Abstracts

Rationale: More than 1.5 million people suffer from traumatic brain injuries (TBI) each year in the U.S. alone. Sequelae of these injuries include both hippocampal hyperexcitability and post-traumatic epilepsy (PTE). However, the mechanisms by which these sequelae develop are not understood at this time. There are currently no pharmacological treatments available to prevent the development of PTE. Previous studies in our laboratory have demonstrated the importance of the endocannabinoid signaling system in the development of hippocampal hyperexcitability after experimental febrile seizures (Chen et al, J Neurosci, Jan 2007). Thus, we sought to investigate whether the endocannabinoid system also plays a critical role in the altered network excitability seen after TBI. Methods: To induce TBI, we used the fluid percussion injury (FPI) model to induce a moderate concussive impact over the sensory cortex. We injected the cannabinoid type I (CB1) receptor antagonist, Rimonabant (SR141716) or vehicle two minutes following the induction of FPI, and allowed the animals to recover. We then used in vivo EEG recording at 6 weeks post-injury to measure post-traumatic hyperexcitability by injecting kainic acid to test seizure threshold. To help determine the mechanism by which Rimonabant decreases hippocampal post-traumatic hyperexcitability, we concomitantly applied Pentobarbital, a barbiturate that can be used to block seizures, in a third group of animals. Results: In vivo assessments of hippocampal hyperexcitability using Kainic acid six weeks after head injury, show a decrease in hyperexcitability with application of Rimonabant (1 mg/Kg or 10 mg/Kg) as compared to vehicle-treated FPI controls. The effect of Rimonabant appears to require neural activity since application of Pentobarbital (40 mg/Kg) plus Rimonabant does not prevent post-traumatic hyperexcitability. Conclusions: These results underscore the significant role of endocannabinoid signaling in the development of post-traumatic hyperexcitability, and reveal the potential of Rimonabant as a novel therapeutic for PTE. This work was funded by a National Institutes of Health Grant NS35915