Oxime-mediated reactivation of organophosphate-inhibited acetylcholinesterase with emphasis on centrally-active oximes

Chambers, Janice E.; Dail, Mary Beth; Meek, Edward C.

doi:10.1016/j.neuropharm.2020.108201

Cited by 10 publications

(6 citation statements)

References 81 publications

(79 reference statements)

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“…In addition, AChE reactivators (briefly oximes) can restore the physiological function of AChE (Bajgar 2004;Colovic et al 2013). Despite all efforts, the effectiveness of oxime therapy is still limited by (i) aging of the enzyme-inhibitor complex, which impedes AChE reactivation, and (ii) poor distribution of oximes into tissues such as the brain (Chambers et al 2020;Kassa 2019;Lorke et al 2008). This especially hampers counteracting the centrally acting agents like soman (pinacolyl methylfluorophosphonate).…”

Section: Introductionmentioning

confidence: 99%

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

Kassa

Karasová

2021

Neurotox Res

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Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.

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Section: Introductionmentioning

confidence: 99%

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

Kassa

Karasová

2021

Neurotox Res

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“…Many other OP insecticides contain P=O bonds and are constitutively active, for example, dichlorphos, while the phosphoramidate insecticide, methamidophos, a metabolite of acephate, has a low ki (Čadež et al, 2021), despite containing a P=O bond and being rapidly lethal in macaques at high doses. While the ki of all “thion” forms is similarly low, the ki for chlorpyrifos oxon is higher than paraoxon and even similar to the nerve agent sarin (Chambers et al, 2020; Worek et al, 2020). In vitro, a 10‐min incubation of parathion and chorpyrifos with 25 μg of P450 and the co‐factor NADPH, resulted in conversion to paraoxon and chlorpyrifos‐oxon sufficient to increase their ki by 50‐fold and 25‐fold, respectively (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

“…However, because the currently approved pyridinium aldoximes are quaternary and do not rapidly diffuse to the brain, many efforts over several decades have been directed to identifying broad spectrum, centrally acting oximes with enhanced ability to mitigate OP toxicity. To date, of the many novel oximes synthesized and evaluated, only a few types have shown the potential to cross the blood–brain barrier (BBB; Chambers et al, 2020). These include pro‐drug analogs of PAM (DeMar et al, 2010), phenoxyalkyl pyridinium detergent‐like oximes (Backer et al, 2022), conjugation of various pyridinium aldoximes to a glucose C‐6 Sox transporter (Garcia et al, 2010), various nucleophiles that encompass association with the active center and peripheral site on AChE (Cadieux et al, 2016; McHardy et al, 2014; Mercey et al, 2012), and low molecular weight zwitterions (Radić et al, 2012; Sit et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

Rosenberg¹,

Garcia

Diener

et al. 2023

Journal of Neurochemistry

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Millions of individuals globally suffer from inadvertent, occupational or self‐harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post‐exposure therapeutic countermeasures generally include administration 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, for example 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 insecticides 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 findings and assess the ability of post‐exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B 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 h 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.image

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“…It is assumed that this is certainly due to the positive charge in the structure and large TPSA. It must be emphasized that a permanent positive charge is an issue of pyridinium oximes since they do not cross the BBB at all or to a sufficient level [ 42 ]. To be more precise, removing the positive charge in some structure refinements of efficient oximes resulted in a better BBB passage [ 43 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands

Gašo-Sokač

Zandona

Roca

et al. 2022

IJMS

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Seven pyridoxal dioxime quaternary salts (1–7) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The synthesis was achieved by the quaternization of pyridoxal monooxime with substituted 2-bromoacetophenone oximes (phenacyl bromide oximes). All compounds, prepared in good yields (43–76%) and characterized by 1D and 2D NMR spectroscopy, were evaluated as reversible inhibitors of cholinesterase and/or reactivators of enzymes inhibited by toxic organophosphorus compounds. Their potency was compared with that of their monooxime analogues and medically approved oxime HI-6. The obtained pyridoxal dioximes were relatively weak inhibitors for both enzymes (Ki = 100–400 µM). The second oxime group in the structure did not improve the binding compared to the monooxime analogues. The same was observed for reactivation of VX-, tabun-, and paraoxon-inhibited AChE and BChE, where no significant efficiency burst was noted. In silico analysis and molecular docking studies connected the kinetic data to the structural features of the tested compound, showing that the low binding affinity and reactivation efficacy may be a consequence of a bulk structure hindering important reactive groups. The tested dioximes were non-toxic to human neuroblastoma cells (SH-SY5Y) and human embryonal kidney cells (HEK293).

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Oxime-mediated reactivation of organophosphate-inhibited acetylcholinesterase with emphasis on centrally-active oximes

Cited by 10 publications

References 81 publications

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides

Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands

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