Oxime-mediated reactivation of organophosphate-inhibited acetylcholinesterase with emphasis on centrally-active oximes. (15th September 2020)

• Record Type: Journal Article
• Authors: Chambers, Janice E.; Dail, Mary B.; Meek, Edward C.
• Is Part Of: Neuropharmacology. Volume 175(2020)
• Publication Date: 2020-09-15
• Subjects: Oxime -- Acetylcholinesterase -- Acetylcholinesterase reactivators -- Organophosphate -- Nerve agent; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108201
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: This review provides an overview of the global research leading to the large number of compounds developed as reactivators of acetylcholinesterase inhibited by a variety of organophosphate compounds, most of which are nerve agents but also some insecticides. A number of these organophosphates are highly toxic and effective therapy by reactivators contributes to saving lives. Two major challenges for more effective therapy with reactivators are identification of a broad spectrum reactivator efficacious against a variety of organophosphate structures, and a reactivator that can cross the blood-brain barrier to protect the brain. The most effective of the reactivators developed are the nucleophilic pyridinium oximes, which bear a permanent positive charge from the quaternary nitrogen in the pyridinium ring. The permanent positive charge retards the oximes from crossing the blood-brain barrier and therefore restoration of normal cholinergic function in the brain is unlikely. A number of laboratories have developed nucleophiles, mostly oximes, that are theorized to cross the blood-brain barrier by several strategies. At the present time, no reactivator is optimally broad spectrum across the wide group of organophosphate chemistries. Some oximes, including the substituted phenoxyalkyl pyridinium oximes invented by our laboratories, have the potential to provide neuroprotection in the brain and show evidence of efficacy against both nerve agent and insecticidal chemistries, so these novel oximes have promise for future development. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'. Highlights: Acetylcholinesterase reactivators are therapeutic for OP poisoning. Most reactivators are nucleophilic pyridinium oximes with positive charges. Several labs are trying to develop brain-penetrating reactivators. Substituted phenoxyalkyl pyridinium oximes show survival efficacy. These oximes show neuroprotection from OP-induced brain damage.