Anticholinesterase toxicity

Tattersall, J.E.H.

doi:10.1016/j.cophys.2018.05.005

Cited by 15 publications

(26 citation statements)

References 80 publications

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“…32 33 1. Introduction 65 Organophosphates and carbamates are potent acetylcholinesterase inhibitors (Colovic, Krstic et al 66 2013, Tattersall 2018). This enzyme is key in terminating the cholinergic transmission that controls 67 neuromuscular junction and important central synapse function (Koelle 1954, Massoulie, Pezzementi 68 et al 1993).…”

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“…The toxicological effect of organophosphates and carbamates is exerted through the covalent 77 modification of acetylcholinesterase (AChE) (Colovic, Krstic et al 2013, Tattersall 2018). The anti-78 cholinesterase drugs are orientated in the catalytic centre of the enzyme in a similar manner to 79 acetylcholine (Dvir, Silman et al 2010).…”

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confidence: 99%

“…This 84 overstimulation of the cholinergic target cells causes a wide range of neurotoxic effects. The first 85 manifestations of the associated cholinergic syndrome cause autonomic disturbances including 86 excessive sweating, lacrimation, salivation as well as cramps, bradycardia and miosis (Jokanovic and 87 Kosanovic 2010, Tattersall 2018). Fatality occurs primarily due to disruption of the respiratory centres 88 in the brain and/or transmission failure at the respiratory muscles (Jokanovic and Kosanovic 2010).…”

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C. eleganspharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes

Izquierdo¹,

O’Connor²,

Green

et al. 2020

Preprint

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34Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-35 cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the 36 overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without 37 intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete 38 efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find 39 better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an 40 excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular 41 junctions show a high degree of molecular and functional conservation with the cholinergic 42 transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, 43 the anti-cholinesterase intoxication of the worm's body wall neuromuscular junction has been 44 unprecedented in understanding molecular determinants of cholinergic function in nematodes and 45 other organisms. We extend the use of the model organism's feeding behaviour as a tool to investigate 46 carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-47 dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the 48 acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay 49 allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole 50 organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-51 cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of 52 the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after 53 inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to 54 explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic 55

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C. eleganspharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes

Izquierdo¹,

O’Connor²,

Green

et al. 2020

Preprint

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“…12 Consequently, compounds that selectively target the nicotinic acetylcholine receptor downstream of AChE inhibition are of therapeutic interest in order to induce normal receptor function despite the accumulated acetylcholine and thus reverse the dysfunctional neural transmission. 92 Nicotinic acetylcholine receptors. As a part of the heterogeneous family of the so-called Cys-loop receptor family, including GABA A -, 5-HT 3 , and Gly-receptors, 93,94 nAChRs are pentameric ligandgated ion channels distributed in the brain, sympathetic and parasympathetic ganglia, epithelial and immune cells, and skeletal muscle.…”

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confidence: 99%

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Amend¹,

Niessen²,

Seeger³

et al. 2020

Annals of the New York Academy of Sciences

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Although 193 states have committed to the Chemical Weapons Convention and 98% of the declared chemical weapons stockpiles have been destroyed so far, nerve agent poisoning remains a lingering threat. The recent dissemination of sarin in Syria, the assassination of Kim Jong-Nam in Malaysia, and the assault on Sergei Skripal in the United Kingdom underline the need for effective treatment. The current therapeutic options of a muscarinic receptor antagonist, an oxime, and an anticonvulsant have been unchanged for decades. Therefore, new therapeutic strategies, for example, bioscavengers and receptor-active substances, are promising concepts that have to be examined for their benefits and limitations. In order to facilitate rapid diagnosis in challenging clinical situations, point-of-care diagnostics and detection are of importance. Therapeutic guidance concerning the duration and success of the current oxime therapy via determination of the cholinesterase status can contribute to an optimal use of resources. In summary, the challenges of current and future therapies for nerve agent poisoning and key diagnostic devices will be discussed.

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“…Deducing the mechanisms underlying toxic syndromes associated with both classes of CWAs is an enduring task (Aas, 2003;Balali-Mood and Abdollahi, 2014;Costanzi et al, 2018;Myhrer and Aas, 2014;Myhrer et al, 2006Myhrer et al, , 2013Myhrer et al, , 2015Timperley and Tattersall, 2015). This is especially true for organophosphorus (OP) compounds which can cause long-term neurological damage (Abdollahi and Karimi-Mojaheri, 2012;Akhgari et al, 2003 Balali-Mood, 2008;Brown and Brix, 1998;Karalleide et al, 2006;Hung et al, 2015;Somani and Husain, 2000;Tattersall, 2018).…”

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