Abstract
Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.
Highlights
Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system
Before World War II (WWII), OPs were developed as chemical warfare nerve agents (NAs) and still pose a great threat in terrorist attacks, as recently witnessed in Syria, Malaysia, and the UK [5, 6]
Exposure to NAs leads to overstimulation of the cholinergic pathway and to the desensitising of the nicotinic and muscarinic cholinergic receptors, which is manifested with severe symptoms of poisoning and can even lead to death [7, 8]
Summary
Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. Organophosphates (OPs) are ester, amide, or thiol derivatives of phosphorous, phosphonic, or phosphinic acids. They occur in important biomolecules like DNA and RNA, some cofactors and coenzymes, phosphoproteins, and phospholipids, but can be synthesised. NAs have fatal effects in the acute phase of poisoning and can cause considerable long-term complications in survivors due to irreversible inhibition of a pivotal enzyme acetylcholinesterase (AChE).
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