Choline derivatives and sodium fluoride protect acetylcholinesterase against irreversible inhibition and aging by DFP and paraoxon

Dehlawi, Mohamed S.; Eldefrawi, Amira T.; Eldefrawi, Mohyee E.; Anis, Nabil A.; Valdés, James J.

doi:10.1002/jbt.2570090506

Cited by 14 publications

(11 citation statements)

References 18 publications

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“…This is also consistent with previous reports that pretreatment of mice with atropine and sodium fluoride has a greater antidotal effect than atropine alone against the toxic actions of soman and sarin (Clement and Filbert 1983;Milatovic and Johnson 1993). Some investigators hypothesized that the antidotal effect of fluoride results from its antidesensitizing action at the nAChRs in the neuromuscular junction and sympathetic ganglia (Dehlawi et al 1994). However, other studies show that compounds with combined antimuscarinic and antinicotinic properties had no effect .…”

Section: Discussionsupporting

confidence: 76%

Targeting Cholinesterase Inhibitor Poisoning with a Novel Blocker Against Both Nicotinic and Muscarinic Receptors

Luo¹,

Ge²,

Cui³

et al. 2009

Neurotox Res

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Clinicians have been treating poisoning by acetylcholinesterase inhibitors (ChEI) for more than half a century. However, the current atropine-centered therapy still cannot protect completely against all ChEIs, and poisoning by ChEIs is fatal in more than 20% of cases. Various solutions that try to enhance atropine's antimuscarinic effects have been used, but these fail to increase the antidotal effect, and their too potent muscarinic antagonism may produce incapacitating side effects. We hypothesized that, in the treatment of ChEI poisoning, the high death rate may not be attributed to the insufficient muscarinic antagonism but to the lack of nicotinic antagonism. To test this hypothesis, we designed and synthesized benthiactzine, a drug that blocks both muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs). A specific [(3)H]quinuclidinyl benzilate-binding assay showed that benthiactzine was much weaker than atropine in binding to five different mAChR subtypes or to mAChRs expressed in 14 different tissues. Electrophysiological measures were used to identify and characterize benthiactzine's antinicotinic effect on three typical neuronal nAChRs subtypes, alpha4beta2, alpha4beta4, and alpha7, which are expressed heterogenously in SH-EP1 cells. Finally, benthiactzine afforded better protection than atropine against the most lethal ChEI, VX or sarin, in a mouse model. These results indicate that the antidotal effect may not be directly related to the antidote's antimuscarinic effect and that the antinicotinic effect may provide additional protection against ChEI poisoning. This new drug may benefit future antidote discovery.

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Section: Discussionsupporting

confidence: 76%

Targeting Cholinesterase Inhibitor Poisoning with a Novel Blocker Against Both Nicotinic and Muscarinic Receptors

Luo¹,

Ge²,

Cui³

et al. 2009

Neurotox Res

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“…It was hypothesised that the antidotal effect of sodium fluoride is due to its antidesensitising action at nicotinic receptors in the neuromuscular junction and sympathetic ganglia, in addition to the proposed increased hydrolysis of sarin and direct detoxification of tabun. Acetylcholinesterase and NTE that had been inhibited with either mipafox or with di-N-butylphosphorodiamidate could be reactivated by prolonged treatment with aqueous potassium fluoride [156]. It is interesting to note that increased cholinesterase levels were observed in workers in a plastic factory handling fluorine compounds [157].…”

Section: Fluoridementioning

confidence: 99%

Organophosphorus poisoning and anaesthesia

1999

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SummaryOrganophosphorus compounds, used as insecticides and agents of chemical warfare, are a major global cause of health problems. These irreversible inhibitors of cholinesterase produce three wellrecognised clinical entities: the initial cholinergic phase, which is a medical emergency often requiring management in an intensive care unit; the intermediate syndrome, during which prolonged ventilatory care is necessary; and delayed polyneuropathy. In addition, disturbances of body temperature and endocrine function, electrolyte imbalances, immunological dysfunction and disorders of reproduction have been reported in animals and man. Vocal cord paralysis, pancreatitis, cardiac arrhythmias and a wide range of neuropsychiatric disorders are known to follow acute and chronic exposure to organophosphorus compounds. As a result of the inhibition of plasma cholinesterase, there can be increased sensitivity to drugs hydrolysed by this enzyme, e.g. suxamethonium and mivacurium. The inhibition of acetylcholinesterase causes dysfunction at the neuromuscular junction which can produce altered responses to nondepolarising neuromuscular blockers. Anaesthetists may encounter patients exposed to organophosphorus compounds either following acute poisoning, trauma (warfare) or as patients with a wide range of nonspecific disorders presenting for surgery. The traditional use of oximes and atropine in treatment has failed to reduce the morbidity and mortality associated with poisoning. The roles of agents that have reduced the toxicity of organophosphorus compounds in animal experiments are discussed as potential therapeutic agents. There is an urgent need for accurate information on the problems associated with exposure to organophosphorus compounds. This would best be achieved by collaborative research between technologically advanced countries and developing countries, where organophosphorus compounds are a leading cause of ill health.

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“…Potentiometric biosensors have been designed based on the measurement of pH change [27,[31][32][33][34][35][36], electrode potential change [37,38] or more sophisticated methods such as ions e l e c t ive fi e l d -e ffect transistor (ISFET) [39][40][41] or lightaddressable potentiometric sensors (LAPS) [42][43][44].…”

Section: Potentiometric Enzyme Sensorsmentioning

confidence: 99%