J Pharmacol Exp Ther. 2023 Aug 29:JPET-AR-2023-001739. doi: 10.1124/jpet.123.001739. Online ahead of print.

ABSTRACT

Organophosphate (OP) compounds are highly toxic and include pesticides and chemical warfare nerve agents (CWNA). OP exposure inhibits the acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-induced SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). In Male Sprague-Dawley rats, we assessed hippocampal pathology and chronic SRS following SE induced by administration of OP agents POX (2 mg/kg, s.c.), DFP (4 mg/kg, s.c.) or GB (2 mg/kg, i.m.), immediately followed by atropine and 2-PAM. At 1-h post-OP-induced SE onset, midazolam was administered to control SE. Approximately 6 months after OP-induced SE, SRS were evaluated using video and EEG monitoring. Histopathology was conducted using Hematoxylin and Eosin (H&E), while silver sulfide (Timm) staining was utilized to assess Mossy Fiber Sprouting (MFS). Across all the OP agents, over 60% of rats that survived OP-induced SE developed chronic SRS. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus. This study demonstrates that OP-induced SE is associated with hippocampal neuronal loss, extensive MFS, and the development of SRS, all hallmarks of chronic epilepsy. Significance Statement Models of OP-induced SE offer a unique resource to identify molecular mechanisms/ pathways contributing to neuropathology and the development of chronic OP morbidities. These models could allow the screening of targeted therapeutics for efficacious treatment strategies for OP toxicities.

PMID:37643794 | DOI:10.1124/jpet.123.001739