Abstracts

Rationale: Accidental or intentional exposure to organophosphates (OP) can cause status epilepticus (SE) and irreversible neural injury. Immediate control of seizure activity is thought to be essential to minimize central nervous system (CNS) neuropathology and the subsequent development of long-term neurological and behavioral disorders. Although the standard of care for OP-induced SE is administration of benzodiazepines, the anticonvulsant effect of these agents is often reported to decrease as the duration of SE is prolonged. However, the effect of delayed treatment with midazolam (MDZ) on CNS neuropathology from OP-induced SE has not been defined. Methods: Male, Sprague Dawley rats (150-200 g) were implanted with electrodes for recording of the electroencephalogram (EEG) 1 week prior to the testing.  On the day of treatment, SE was induced by administration of diisopropyl fluorophosphate (DFP).  At 30, 60 or 120 min after the start of SE, rats were administered MDZ (2 mg/kg) to treat SE.  EEG was recorded for 24 hr, at which time the rats were perfused, and the brains were sectioned and labeled with Fluoro-Jade B (FJB). Neuropathology was assessed as the number of FJB positive cells in 10 brain regions: dorsal CA1, dorsal CA3, hilus, ventral CA1, ventral CA3, amygdala, thalamus, and the parietal, entorhinal and piriform cortices.     Results: At 30, 60 and 120 min after the start of SE, MDZ treatment significantly reduced both seizure power as well as EEG spike frequency for several hours.   However, at all three time points, MDZ did not completely terminate electrographic SE. Treatment with MDZ had a minimal effect on neuronal death.  The number of FJB-labeled neurons for most of the 10 counted brain regions was similar regardless of time of treatment, but an average reduction of approximately 30% in treated rats compared to untreated rats was observed when data from all 10 of the brain regions was combined.    Conclusions: These data demonstrate that treatment of OP-induced SE by MDZ can be delayed by as much as 120 min.  MDZ was effective in reducing the ongoing electrographic SE, but this treatment alone was insufficient to completely stop seizures.  Likewise, MDZ treatment resulted in a minimal reduction in cell death throughout the brain when SE was left untreated for at least 30 min. Funding: This research was supported by the NIH Office of the Director through an Inter-Agency Agreement (Y1-O6-9613-01) between the National Institute of Allergy and Infectious Diseases (NIAID) and DoD USAMRICD (A120-B.P2009-2) and under subcontract W81XWH- 14-C-0119 to the University of Utah.