Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates. (2nd January 2016) - Chambers, Janice E.
Highlights: Novel oxime reactivators that show ability to cross the blood–brain barrier at high sublethal dosages of surrogates for the nerve agents sarin and VX also can prevent lethality of these surrogates in rats. The novel oximes also attenuate seizure-like behavior induced by lethal level sarin and VX surrogates. This novel oxime platform has promise for development as antidotes that can both save lives and provide neuroprotection. Abstract: Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6 mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65 mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24 h to all tested rats when they received only 0.65 mg/kg atropine at the time of initiation of seizure-like behavior (about 30 min). If 146 mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8 h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24 h survivors. The lethality data indicate that 24 h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures.