Abstracts

Rationale: The incidence of traumatic brain injury (TBI) in the U.S. has reached epidemic proportions, with more than 1.5 million people suffering from TBI each year. Sequeale of TBI includes seizures, hippocampal hyperexcitability and post-traumatic epilepsy (PTE); however, the mechanisms by which hyperexcitability or epileptogenesis occur are not understood at this time. In addition, there are no pharmacological treatments available to prevent the development of PTE. Previous studies in our laboratory have shown the importance of the endocannabinoid signaling system in the development of hippocampal hyperexcitability after experimental febrile seizures. Armed with this insight, we sought to investigate if the endocannabinoid system also plays a critical role in the altered network excitability seen after head injury the fluid percussion injury (FPI) model of TBI. Here, we describe that post-traumatic hyperexcitability can be decreased with the application of the CB1 receptor antagonist SR141716 (SR; Rimonabant) 2 minutes after FPI.Methods: Wistar rats (P21) were subjected to moderate FPI and injected with SR (1mg/Kg), or control saline, 2 minutes post-injury. Post-traumatic hyperexcitability was then assessed electrophysiologically both in vitro and in vivo. Results: In vitro assessments of DG hyperexcitability show that application of SR results in a decrease in hyperexcitability in SR treated animals as compared to vehicle treated controls. In vivo assessements of hippocampal hyperexcitability suggest that SR treatment results in an increased latency to Kainic acid induced seizures in SR treated animals.Conclusions: These results indicate the significant role endocannabinoid signaling plays in the development of post-traumatic hyperexcitability and reveal the potential of SR as a novel therapeutic for PTE. This work is supported by the National Institutes of Health grant NS35915-09 (I.S.)