Acetylcholinesterase inhibition preventing

A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with reversible enzyme inhibitors to prevent binding of the irreversible organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess. 

Duran, R., Cervenansky, C., Dajas, F., Tipton, K.F. (1994). Fasciculin inhibition of acetylcholinesterase is prevented by chemical modification of the enzyme at a peripheral site. Biochim. Biophys. Acta 1201 381-8. 

Cholinesterase inhibitors increase parasympathetic nervous system (cholinergic) activity indirectly by inhibiting acetylcholinesterase, thereby preventing the breakdown of acetylcholine. They are only effective in the presence of acetylcholine. They are listed in Table 1. 

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. 

The actions of acetylcholine are terminated in the synaptic cleft primarily by acetylcholinesterase, which cleaves the transmitter at the ester bond. The agents in Table 2.6 inhibit acetylcholinesterase, thus preventing transmitter (acetylcholine) degradation. 

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). 

Diabetic patients have reduced antioxidant defences and suffer from an increased risk of free radical-mediated diseases such as coronary heart disease. EC has a pronounced insulin-like effect on erythrocyte membrane-bound acetylcholinesterase in type II diabetic patients (Rizvi and Zaid, 2001). Tea polyphenols were shown to possess anti-diabetic activity and to be effective both in the prevention and treatment of diabetes (Choi et al, 1998 Yang et al, 1999). The main mechanism by which tea polyphenols appear to lower serum glucose levels is via the inhibition of the activity of the starch digesting enzyme, amylase. Tea inhibits both salivary and intestinal amylase, so that starch is broken down more slowly and the rise in serum glucose is thus reduced. In addition, tea may affect the intestinal absorption of glucose. 

Substances that block the serine residue in the active center of acetylcholinesterase [2j—e.g., the neurotoxin E605 and other organophosphates—prevent ACh degradation and thus cause prolonged stimulation of the postsynaptic cell. This impairs nerve conduction and muscle contraction. Curare, a paralyzing arrow-poison used by South American Indians, competitively inhibits binding of ACh to its receptor. 

Acetylcholinesterase can be inhibited by two general mechanisms. In the first mechanism, positively charged quaternary ammonium compounds bind to the anionic site and prevent ACh from binding—a simple competitive inhibition. In the second mechanism, the agents act either as a false substrate for the cholinesterase or directly attack the esteratic site in both cases they covalently modify the esteratic site and non-competitively prevent further hydrolytic activity. Either mechanism can be effective in preventing the hydroly-... 

Mechanism of Action A cholinergic drug that prevents destruction of acetylcholine by inhibiting the enzyme acetylcholinesterase, thus enhancing impulse transmission across the myoneural junction. Therapeutic Effect Improves intestinal and skeletal muscle tone stimulates salivary and sweat gland secretions. 

Ser residue in the active site of the enzyme acetylcholinesterase, irreversibly inhibiting the enzyme and preventing the transmission of nerve impulses (Fig. la). Iodoacetamide modifies Cys residues and hence may be used as a diagnostic tool in determining whether one or more Cys residues are required for enzyme activity (Fig. lb). The antibiotic penicillin irreversibly inhibits the glycopeptide transpeptidase enzyme that forms the cross-links in the bacterial cell wall by covalently attaching to a Ser residue in the active site of the enzyme (see Topic Al). 

Anatoxin-a(s) inhibits acetylcholinesterase by acting as an irreversible active-site-directed inhibitor [61]. This prevents degradation of ACh and leads to over-stimulation of the muscle cells (Figure 6.1) [56,62]. Thus, although the mechanism of action of anatoxin-a(s) is quite different from that of anatoxin-a, the observed toxicity is similar. In addition, it was the first irreversible acetylcholinesterase inhibitor to be found in a cyanobacterium. 

Luo, C., Saxena, A., Smith, M., Garcia, G., Radic, Z., Taylor, P., Doctor, B.P. (1999). Phosphoryl oxime inhibition of acetylcholinesterase during oxime reactivation is prevented by edrophonium. Biochemistry 38 9937-47. 

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