Epilepsia 2014-12-01

sec-Butyl-propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon-induced status epilepticus in rats.

Guy Bar-Klein, Evyatar Swissa, Lyn Kamintsky, Tawfeeq Shekh-Ahmad, Rotem Saar-Ashkenazy, Yechiel Hubary, Shai Shrot, Liran Stetlander, Arik Eisenkraft, Alon Friedman, Meir Bialer

Index: Epilepsia 55(12) , 1953-8, (2014)

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Abstract

Organophosphates (OPs) are commonly used insecticides for agriculture and domestic purposes, but may also serve as nerve agents. Exposure to OPs result in overstimulation of the cholinergic system and lead to status epilepticus (SE), a life-threatening condition that is often resistant to treatment. SE is associated with significant neuronal damage, neurocognitive dysfunction, and the development of lifelong epilepsy. Therefore, rapid termination of SE and prevention of brain damage is of high interest. Here we tested the efficacy of sec-butyl-propylacetamide (SPD) and two of its individual stereoisomers, (2S,3S)-SPD and (2R,3R)-SPD, in discontinuing OP-induced seizures. SPD is a one carbon homolog of valnoctamide, a central nervous system (CNS)-active constitutional isomer of valproic acid (VPA) corresponding amide valpromide.Rats were implanted with epidural telemetric electrodes to allow electrocorticography (ECoG) recording 24 h prior, during and 24 h aft50 Median lethal dose). All rats were provided with antidotal treatment of atropine and toxogonin. Epileptic activity was measured using a novel automated system to evaluate the different effects of midazolam, SPD, and its individual stereoisomers in comparison to nontreated controls.Treatment with SPD or its individual stereoisomer (2S,3S)-SPD significantly shorten paraoxon-induced SE and reduced the duration of recorded pathologic activity after SE was terminated. (2S,3S)-SPD was superior to racemic-SPD in diminishing delayed pathologic epileptiform activity within the first 8 h after SE.These results suggest SPD as an efficient drug for the rapid termination of SE and pathological epileptiform activity following OP poisoning, a strategy to reduce neuronal dysfunction and the risk for lifelong epilepsy.Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.