Treatment of Status Epilepticus: A Translational Proposal

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DESCRIPTION (provided by applicant): Treatment Of Status Epilepticus: A Translational Proposal Epilepsy is the most common diagnosis in VA outpatient clinics, and the large number of traumatic brain injuries in OEF/OIF is expected to result in a significant increase in its frequency among veterans. This study translates our investigations of the role of receptor trafficking in experimental SE into principles of treatment, using drugs available in the US pharmacopeia. Treatment of status epilepticus (SE) remains ineffective, with a mortality of 27% in recent population-based studies. Once seizures have started, they become self-sustaining, independent of their original trigger, and develop time-dependent pharmacoresistance. Our work (Naylor et al J Neurosci 2005) has shown that repeated seizures cause an internalization (and temporary inactivation) of synaptic GABAA receptors and an increase in synaptic NMDA receptors, which both result from seizure-induced, maladaptive receptor trafficking. These changes suggest a mechanism for the development of self-sustaining seizures (fewer GABAA receptors and more NMDA receptors in synapses) and for pharmacoresistance (fewer synaptic targets for GABAergic drugs). They also suggest that, in SE, polytherapy is more likely to be successful than monotherapy (the current gold standard), since treatment should have at least 2 targets: GABAA receptors (either preventing their internalization and/or maximally stimulating those that are left in the synapse), and NMDA receptors (preventing their movement to the synapse, or reducing their activity). Combination treatments aimed at the GABAA and NMDA systems simultaneously have not been tested extensively. Our preliminary studies explored the use of such combinations, using drugs which are currently approved for human use or are close to approval, and were able to stop severe experimental SE with low subanesthetic doses of anticonvulsants. Therapeutic success with this receptor-based approach to drug selection would confirm the importance of receptor trafficking in the pathophysiologiy of SE, and could greatly improve the effectiveness of treatment of SE. We will induce SE chemically with lithium and pilocarpine, or electrically by stimulating the perforant path, and will treat at 3 time points: after the second intense seizure, 30minutes after seizure onset, or 2 hours after seizure onset. Electroencephalogram and behavior will be recorded for 24 hours and analyzed with appropriate software. Acute histological outcome will be assessed at 72 hours, chronic epileptogenesis, behavior and histology will be studied > 3 months after SE. The importance of timing of treatment will be studied. Our preliminary results suggest that combinations of low doses of anticonvulsants which include GABAA agonists and NMDA blockers are far more effective than monotherapy with the same agents in stopping severe experimental SE, and we hope that the principles of treatment established in this study will lead to improvements in the way we treat status epilepticus clinically. PUBLIC HEALTH RELEVANCE: NARRATIVE Status epilepticus affects 126,000 to 195,000 cases a year in the USA, with an estimated mortality of 22- 42,000 patients yearly. It is one of the most common neurological emergencies in V.H.A. Emergency Rooms, and indeed the largest study of status epilepticus ever carried out was a VA Cooperative study. Status epilepticus is also a frequent consequence of traumatic brain injury (TBI), the most frequent physical injury in OEF/OIF veterans.