Abstract
Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.
Highlights
Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year
OP compounds act as irreversible inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase leading to the excessive accumulation of acetylcholine (ACh) in synapses and the subsequent overstimulation of cholinergic receptors[6]
Emergency therapy for OP poisoning consists of atropine to prevent overstimulation of muscarinic acetylcholine receptors, oximes to reactivate the activity of cholinesterases and benzodiazepines to control seizures caused by weaponized OP compounds[7]
Summary
Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 μM). OP compounds act as irreversible inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase leading to the excessive accumulation of acetylcholine (ACh) in synapses and the subsequent overstimulation of cholinergic receptors[6]. Emergency therapy for OP poisoning consists of atropine to prevent overstimulation of muscarinic acetylcholine receptors (mAChRs), oximes to reactivate the activity of cholinesterases and benzodiazepines to control seizures caused by weaponized OP compounds[7]
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