Neuroprotection From Organophosphate-Induced Damage by Novel Phenoxyalkyl Pyridinium Oximes in Rat Brain.

Abstract

The nerve agents are extremely toxic organophosphates which lead to massive inhibition of acetylcholinesterase (AChE) in both the central and peripheral nervous systems. The currently approved pyridinium oxime reactivators of organophosphate-inhibited AChE (eg, 2-PAM in the United States) cannot penetrate the blood-brain barrier because of the permanent positive charge in the pyridinium ring. Therefore these current oximes cannot rescue inhibited AChE in the brain. Our laboratories have invented and patented a platform of substituted phenoxyalkyl pyridinium oximes that have been tested for efficacy as therapy within the brains of adult male rats which were challenged with a high sublethal dosage of highly relevant surrogates of sarin (nitrophenyl isopropyl methylphosphonate, NIMP) and VX (nitrophenyl ethyl methylphosphonate, NEMP). The histochemical astrocyte marker glial fibrillary acidic protein (GFAP) was investigated as an indication of neuropathology in two brain regions, the piriform cortex and the dentate gyrus of the hippocampus, which are regions known to be damaged by nerve agent toxicity. Rats treated with either NIMP or NEMP without therapy or with NIMP or NEMP plus 2-PAM therapy showed similar increases in GFAP compared with vehicle controls. However, the rats challenged with NIMP or NEMP plus therapy with our novel Oxime 20 (either a bromide or a mesylate salt) showed GFAP levels statistically undistinguishable from controls. These data provide highly supportive functional evidence of novel oxime entry into the brain. These novel oximes have the potential to provide central neuroprotection from organophosphate anticholinesterase-induced damage, which is a characteristic not displayed by most pyridinium oximes.