Abstracts

Rationale: Organophosphorous (OP) exposure hyperactivates the cholinergic system through the inhibition of acetylcholinesterase (AChE), causing hypersecretions, fasciculations, tremors, convulsions, coma, and death. Despite advances in treatment against OP- exposure, current regimens fail to prevent status epilepticus (SE) and neuropathology from patients exposed to OP. Histone deacetylases (HDAC) remove acetyl groups from lysine residues and shut off chromatin transcriptional mechanisms, affecting gene activity and cellular processes. HDAC inhibitors interfere with these mechanisms and are thought to regulate certain genes through epigenetic pathways, potentially increasing neuroprotective protein expression in the brain. Valproic acid (VPA), an HDAC1 inhibitor, has shown cortical neuron protection in recent studies, is associated with an increase in histone-H3 acetylation levels, and offers potential therapeutic mitigation against soman-induced seizures and neuropathology. Methods: Male Sprague-Dawley rats were implanted with telemetry transmitters (Data Sciences International - DSI, St. Paul, MN - F40 EET transmitter) that recorded cortical EEG, motor activity and temperature 24 hours/day immediately after surgery. After a minimum surgical recovery of 7 days, rats were transported to USAMRICD and stabilized over the weekend. On the day of exposure, animals were pretreated with the oxime HI-6 (125 mg/kg, i.p.) 30 min prior to soman injection (110 µg/kg, s.c.). Rats were injected with the anticholinergic atropine SO4 (2 mg/kg, i.m.) one min after soman exposure to block muscarinic receptor activation. Diazepam (DZP, 10 mg/kg, s.c.), a benzodiazepine, was injected 30 min post SE onset. VPA (25, 50 and 75 mg/kg; i.p.) or vehicle was administered 30, 60, and 180 min after SE onset. Animals were euthanized 72 hours or 15 days after exposure, brains were removed, and processed with Nissl, Silver and Fluoro-Jade B staining. Time spent in electrographic seizures was estimated through the use of a customized MATLAB program (Mathworks, Vers. 7) and confirmed by visual screening. Results: Animals that showed prolonged SE also presented spontaneous recurrent seizures (SRS). The time spent in seizures was not significantly different between control rats (One-way ANOVA p>0.05) and treated rats at the currently tested doses. Core body temperature was significantly different between treated rats (One Way ANOVA p<0.01) and multiple comparison analysis showed a significant decrease in core body temperature with VPA , 75 mg/kg, animals compared to controls (One Way ANOVA, p < 0.05).