Acetylcholine acetylcholinesterase inhibition

Ecothiophate iodide and denecarium bromide inhibit acetylcholinesterase. Inhibition of this enzyme increases the availability of acetylcholine at the nerve junction, thus increasing the stimulation of the muscarinic (M3) receptors of the ciliary... 

Increased levels of urinary catecholamines may also be associated with accumulation of acetylcholine that resulted from acetylcholinesterase inhibition by disulfoton. No human data were located to support this, but limited animal data provide some evidence. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in rats, respectively, within 72 hours (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). 

Herzog CD, Nowak KA, Sarter M, Bruno JP. 2003. Microdialysis without acetylcholinesterase inhibition reveals an age-related attenuation in stimulated cortical acetylcholine release. Neurobiol Aging 24(6) 861-863. 

M.B. Skaddan, M.R. Kilbourn, S.E. Snyder, P.S. Sherman, Acetylcholinesterase inhibition increases in vivo N-(2-[ F]fluoroethyl)-4-piperidyl benzilate binding to muscarinic acetylcholine receptors, J. Cereb. Blood Flow Metab. 21 (2001) 144-148. 

Anatoxin-a(s) is a phosphate ester of a cyclic iV-hydroxyguanidine (Fig. 16.2) [5]. It is the only natural organophosphate known and, as the synthetic parathion and malathion, irreversibly inhibits acetylcholinesterase. When this enzyme is inhibited, acetylcholine is no longer hydrolysed, the postsynaptic membrane cannot be repolarised, the nerve influx is blocked and the muscle cannot be contracted. 

The authors speculated that the antimuscarinic drugs impaired the cholinergic receptor down-regulation that would normally occur in the presence of the increased concentrations of acetylcholine caused by acetylcholinesterase inhibition. Withdrawal of the antagonist therefore abruptly exposed the receptors to high concentrations of the neurotransmitter, leading to seizures. 

H-Chlorpyrifos oxon binds covalently to rat heart M2 musearinic receptors (Bomser and Casida, 2001). The site of attachment has not been identified. When guinea pigs were treated with chlorpyrifos, diazinon, or parathion at doses too low to inhibit acetylcholinesterase activity, the M2 muscarinic receptors lost their abihty to inhibit acetylcholine release from parasympathetic nerves, causing bronchocon-striction (Lein and Fryer, 2005). 

Carbofuran is an inhibitor of acetylcholinesterase. Inhibition of acetylcholinesterase activity leads to an increase in acetylcholine at the nerve synapse resulting in excessive cholinergic stimulation. Following intravenous injection of 50pgkg in rats, blood acetylcholinesterase activity was depressed by 83% within 2 min. With oral exposures, acetylcholinesterase activity was depressed by 37% within 15 min of ingestion. Recovery of acetylcholinesterase activity parallels carbofuran elimination. 

Like other organophosphorus insecticides, the active metabolite, diazoxon, elicits toxicity by inhibiting the enzyme acetylcholinesterase in the cholinergic synapse. Acetylcholinesterase inhibition leads to accumulation of the neurotransmitter acetylcholine resulting in neurotoxicity. 

Reversible and competitive acetylcholinesterase inhibition leading to an increased concentration of acetylcholine at cholinergic synapses modulates nicotinic acetylcholine receptor may increase glutamate and serotonin levels APOE, APP... 

Hemendmince oj mechanisms past. Acetylcholinesterase converts acetylcholine into acetate and choline. Like serine proteases, acetylcholinesterase is Inhibited by DIPF. Propose a catalytic mechanism for acetylcholine digestion by acetylcholinesterase. Show the reaction as chemical structures. 

Acetylcholinesterase. Altered acetylcholinesterase less sensitive to organophosphorus and carbamate insecticides has been observed in a wide variety of insects and mites (51). Acetylcholinesterase inhibiting insecticides phosphorylate or carbamylate the serine residue in the active site of the enzyme preventing vital catalysis of acetylcholine. Resistance due to reduced sensitivity to inhibition of this target enzyme has been found in house fly, mosquitoes, green rice leafhopper, and both phytophagous and predacious species of mites. 

Acetylcholine, deactivation by acetylcholinesterase, 469-470 Acetylcholinesterase, inhibition of acetylcholine, 469-470,471/... 

Diethyl 0-(3-methyl-5-pyrazolyl) phosphate (722) and 0,0-diethyl 0-(3-methyl-5-pyrazolyl) phosphorothioate (723) were prepared in 1956 by Geigy and they act, as do all organophosphates in both insects and mammals, by irreversible inhibition of acetylcholinesterase in the cholinergic synapses. Interaction of acetylcholine with the postsyn-aptic receptor is therefore greatly potentiated. 0-Ethyl-5-n-propyl-0-(l-substituted pyrazol-4-yl)(thiono)thiolphosphoric acid esters have been patented as pesticides (82USP4315008). 

An enzymatic assay can also be used for detecting anatoxin-a(s). " This toxin inhibits acetylcholinesterase, which can be measured by a colorimetric reaction, i.e. reaction of the acetyl group, liberated enzymatically from acetylcholine, with dithiobisnitrobenzoic acid. The assay is performed in microtitre plates, and the presence of toxin detected by a reduction in absorbance at 410 nm when read in a plate reader in kinetic mode over a 5 minute period. The assay is not specific for anatoxin-a(s) since it responds to other acetylcholinesterase inhibitors, e.g. organophosphoriis pesticides, and would need to be followed by confirmatory tests for the cyanobacterial toxin. 

FIGURE 5.46 Interaction of the serine hydroxyl residue in the catalytically active site of acetylcholinesterase enzyme with esters of organophosphates or carbamates. The interaction leads to binding of the chemical with the enzyme, inhibition of the enzyme, inhibition of acetylcholine hydrolysis, and thus accumulation of acetylcholine in the synapses. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

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