Efforts toward treatments against aging of organophosphorus‐inhibited acetylcholinesterase

Abstract

Aging is a dealkylation reaction of organophosphorus (OP)-inhibited acetylcholinesterase (AChE). Despite many studies to date, aged AChE cannot be reactivated directly by traditional pyridinium oximes. This review summarizes strategies that are potentially valuable in the treatment against aging in OP poisoning. Among them, retardation of aging seeks to lower the rate of aging through the use of AChE effectors. These drugs should be administered before AChE is completely aged. For postaging treatment, realkylation of aged AChE by appropriate alkylators may pave the way for oxime treatment by neutralizing the oxyanion at the active site of aged AChE. The other two strategies, upregulation of AChE expression and introduction of exogenous AChE, cannot resurrect aged AChE but may compensate for lowered active AChE levels by in situ production or external introduction of active AChE. Upregulation of AChE expression can be triggered by some peptides. Sources of exogenous AChE can be whole blood or purified AChE, either from human or nonhuman species.

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [18F]‐VXS

“…Hence, efforts to expand the platform in other animal species, including primates, are ongoing and those results will be reported in due course. With the examination of new and existing oximes, pretreatments, and scavengers to counteract the OP exposures and toxicity, 1,2,7,8,[61][62][63][64][65][66][67] this platform deploying quantitative OP tracer PET imaging will help to ascertain the utility of these new candidate therapeutics.…”

Evaluation of Copeptin level and Peradeniya Score as Predictors of Severity and Outcome in Acute Organophosphorus Pesticides Poisoned Patients Admitted to the Poison Control Center Ain Shams University Hospitals (A Prospective Study)

“…Cholinestrase (ChE) reactivators known as oximes react with the phosphorus atom of OP attached at the enzyme, then oxime phosphate is formed resulting in reactivated ChE. Also, oximes slow the ageing of the phosphorylated enzyme complex and convert OP to a harmless compound (Zhuang et al, 2016).…”

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

“…Most medical countermeasures for the "treatment" of OP exposurea im to minimize the cholinergic crisis upon deactivation of acetylcholinesterase (AChE) at the neurosynaptic and neuromuscular junctionso rt or emove the OP toxicant by some scavenging process. [88] Clinically,O Pp oisoningi sc urrently "treated" by ac ombination of anti-cholinergic drugs (e.g.,a tropine) and oximes (e.g.,2 -PAM). Atropine acts as an antagonist of muscarinic acetylcholine receptors, while oximes (more likely,t heir deprotonated forms,t he oximates) substitute the phosphylated serine in an ucleophilic manner,t hereby reactivating the OP-inhibited form of AChE.…”

“…[145,146] Multiple attempts were made to convert the phosphylated oxyanion aged form to ar e-alkylated (i.e.,i nhibited) form of AChE using av arietyo fa lkylating reagents,i ncluding sulfonates, haloketones, methoxypyridniums,a nd sulfoniums. [88,[145][146][147][148][149][150][151] However,w hile some of these alkylating strategies were effective in model systems, thesea ttempts proved to be unsuccessfulw hen they were attempted in vitro with aged AChE.…”