Paper Report for: Rosenberg_2023_J.Neurochem__

Millions of individuals globally suffer from inadvertent, occupational or self-harm exposures from organophosphate (OP) insecticide exposures; significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include admin-istration of atropine with an oxime, to reactivate the OP-inhibited AChE. However, animal model studies and recent clinical trials using insecticide-poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently-used oximes either reactivate poorly, do not readily cross the blood brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure eg RS194B have been developed that efficiently cross the BBB resulting in reactivation of OP-inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticide or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these studies and assess the ability of post-exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos, which require oxidation by P450 in the liver to convert inactive thions to the active toxic oxon forms, and once again demonstrated its efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1-2 hours was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non-invasive treatment, especially in isolated rural settings.