Comparison of spontaneous recurrent seizures in rats following status epilepticus induced by organophosphate paraoxon, DFP, and sarin

Abstract

Organophosphate (OP) compounds are highly toxic and include household, industrial, agricultural, and chemical warfare nerve agents (CWNA). OP exposure inhibits acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). Here we assessed hippocampal pathology and chronic SRS following SE induced by OP agents in rats. Male Sprague-Dawley rats were injected with 1.5x LD50 of various OP agents, followed by atropine and 2-PAM. At 1-h post-OP-SE onset, midazolam was administered to control SE. Approximately 6 months following OP-SE, SRS were evaluated using continuous video-EEG monitoring. Histopathology was conducted using Hematoxylin and Eosin (H&E), while silver sulfide (Timm) staining was utilized to assess Mossy Fiber Sprouting (MFS). Over 60% of OP-SE surviving rats developed SRS with varying seizure frequencies, durations, and Racine severity scores. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus of SRS-expressing OP-SE rats. This study demonstrates that OP-SE is associated with hippocampal neuronal loss, extensive MFS, and SRS, all hallmarks of chronic epilepsy.