Electro-behavioral phenotype and cell injury following exposure to paraoxon-ethyl in mice: Effect of the genetic background.

Organophosphorus compounds (OP) are irreversible inhibitors of both central and peripheral cholinesterases (ChE). They still represent a major health issue in some countries as well as a terrorist and military threat. In order to design appropriate medical counter-measures, a better understanding of the pathophysiology of the poisoning is needed. Little to nothing is known regarding the impact of the genetic background on OP-induced seizures and seizure-related cell injury. Using two different mouse strains, Swiss and C57BL/6J, exposed to a convulsing dose of the OP pesticide paraoxon-ethyl (POX), our study focused on seizure susceptibility, especially the occurrence of SE and related mortality. We also evaluated the initial neuropathological response and SE-induced cell injury. Following the administration of 2.4 mg/kg POX, more Swiss mice experienced SE than C57BL/6J (55.6% versus 17.2%) but the duration of their SE, based on EEG recordings, was shorter (64.3 ±â€¯19.5 min versus 180.8 ±â€¯36.8 min). No significant difference was observed between strains regarding mortality (33% versus 14%). In both strains limited cell injury was observed in the medial temporal cortex, the dentate gyrus and the CA3 field without inter-strain differences (Fluorojade C-positive cells/mm2). Conversely, only C57BL/6J mice showed cell injury in the CA1 field. There was no obvious correlation between the number of Fluorojade C-positive cells and the duration of the EEG discharges. Our work suggests some differences between Swiss and C57BL/6J mice and lay ground to further studies on the impact of strains in the development of central nervous system toxicity of OP.

Treatment of status epilepticus with ketamine, are we there yet?

Status epilepticus (SE), a neurological emergency both in adults and in children, could lead to brain damage and even death if untreated. Generalized convulsive SE (GCSE) is the most common and severe form, an example of which is that induced by organophosphorus nerve agents. First- and second-line pharmacotherapies are relatively consensual, but if seizures are still not controlled, there is currently no definitive data to guide the optimal choice of therapy. The medical community seems largely reluctant to use ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate glutamate receptor. However, a review of the literature clearly shows that ketamine possesses, in preclinical studies, antiepileptic properties and provides neuroprotection. Clinical evidences are scarcer and more difficult to analyze, owing to a use in situations of polytherapy. In absence of existing or planned randomized clinical trials, the medical community should make up its mind from well-conducted preclinical studies performed on appropriate models. Although potentially active, ketamine has no real place for the treatment of isolated seizures, better accepted drugs being used. Its best usage should be during GCSE, but not waiting for SE to become totally refractory. Concerns about possible developmental neurotoxicity might limit its pediatric use for refractory SE.