PT  - JOURNAL ARTICLE
AU  - Asheebo Rojas
AU  - Wenyi Wang
AU  - Avery Glover
AU  - Zahra Manji
AU  - Yujiao Fu
AU  - Raymond Dingledine
TI  - Beneficial Outcome of Urethane Treatment following Status Epilepticus in a Rat Organophosphorus Toxicity Model
AID  - 10.1523/ENEURO.0070-18.2018
DP  - 2018 Apr 16
TA  - eneuro
PG  - ENEURO.0070-18.2018
4099  - http://www.eneuro.org/content/early/2018/04/16/ENEURO.0070-18.2018.short
4100  - http://www.eneuro.org/content/early/2018/04/16/ENEURO.0070-18.2018.full
AB  - The efficacy of benzodiazepines to terminate electrographic status epilepticus (SE) declines the longer a patient is in SE. Therefore, alternative methods for ensuring complete block of SE and refractory SE are necessary. We compared the ability of diazepam and a subanesthetic dose of urethane to terminate prolonged SE and mitigate subsequent pathologies. Adult Sprague-Dawley rats were injected with diisopropylfluorophosphate (DFP) to induce SE. Rats were administered diazepam (10 mg/kg, ip) or urethane (0.8 g/kg, sc) one hour after DFP-induced SE and compared to rats that experienced uninterrupted SE. Large amplitude and high frequency spikes induced by DFP administration were quenched for at least 46 hr in rats administered urethane one hour after SE onset as demonstrated by cortical electroencephalography (EEG). By contrast, diazepam interrupted SE but seizures with high power in the 20-70Hz band returned 6-10 hr later. Urethane was more effective than diazepam at reducing hippocampal neurodegeneration, brain inflammation, gliosis and weight loss as measured on day 4 after SE. Furthermore, rats administered urethane displayed a 73% reduction in the incidence of spontaneous recurrent seizures after 4-8 weeks and a 90% reduction in frequency of seizures in epileptic rats. By contrast, behavioral changes in the light-dark box, open field and a novel object recognition task were not improved by urethane. These findings indicate that in typical rodent SE models it is the return of SE overnight, and not the initially intense 1-2 hr SE experience, that is largely responsible for neurodegeneration, accompanying inflammation, and the subsequent development of epilepsy.Significance Delayed medical care to patients exposed to high levels of an organophosphorus (OP) agent can lead to the development of seizures and/or status epilepticus, which if left untreated results in neuropathologies and the inevitable development of epilepsy in surviving rats. Administration of the general anesthetic, urethane following DFP induced status epilepticus produced a number of beneficial consequences. Urethane effectively terminated electrographic status epilepticus, reduced neuroinflammation, neurodegeneration and astrogliosis, accelerated weight regain within 4 days after DFP exposure, and reduced the incidence and frequency of spontaneous recurrent seizures. This study gives insight into therapeutic modalities for the treatment of status epilepticus.