Acetylcholinesterase inhibition prolonged

Enzymatic inactivation of transmitter Neostigmine Cholinergic synapses (acetylcholinesterase) Inhibits enzyme prolongs and intensifies transmitter action... 

Acetylcholinesterase inhibition caused by azinphos-methyl can persist for a long time (2-6 weeks). Repeated chronic exposure may therefore result in prolonged acetylcholinesterase inhibition that may lead to flu-like illnesses. 

Anticholinesterase A drug that inhibits the enzyme acetylcholinesterase, which normally inactivates acetylcholine at the synapse. The effect of an anticholinesterase (or cholinesterase inhibitor) is thus to prolong the duration of action of the neurotransmitter. An example is rivastigmine, used in the treatment of Alzheimer s disease. 

Most insecticides, especially the organophosphate group, cause neurotoxicity as their major mode of action. Assessment of the neurotoxicity includes neurochemical endpoints such as cholinesterase (including acetylcholinesterase, which is the major neurotransmitter in vertebrates such as fish, and other enzymes such as butyrylcholinesterase) inhibition and behavioral endpoints such as swimming speed [79]. Studies done in rats show the neurotoxic action of insecticides such as dimethoate, methyl parathion, dichlorvos, ethyl parathion or propoxur after a prolonged exposure [80,81]. 

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. 

Acetylcholine is a neurotransmitter that functions in conveying nerve impulses across synaptic clefts within the central and autonomic nervous systems and at junctures of nerves and muscles. Following transmission of an impulse across the synapse by the release of acetylcholine, acetylcholinesterase is released into the synaptic cleft. This enzyme hydrolyzes acetylcholine to choline and acetate and transmission of the nerve impulse is terminated. The inhibition of acetylcholineasterase results in prolonged, uncoordinated nerve or muscle stimulation. Organophosphorus and carbamate pesticides (Chapter 5) along with some nerve gases (i.e., sarin) elicit toxicity via this mechanism. 

The enzyme acetylcholinesterase (AChE) is localized at the synapse and degrades ACh released by the presynaptic nerve, thus limiting its actions. Inhibition of the effects of AChE (e.g. with a cholinesterase inhibitor such as physo-stigmine) prolongs the time course of action of ACh or of stimulation of the presynaptic nerve. 

Organophosphate and carbonate pesticides act by inhibiting the enzyme acetylcholinesterase, which hydrolyzes acetylcholine, a neurotransmitter. This inhibition in the CNS or peripheral nervous system prolongs the action at the neuron s synaptic receptors and produces clinically measurable overstimulation symptoms that include muscle weakness, perspiration, tremor, blurred vision, and salivationJ6l More than 90 different organophosphate pesticides have been identified J7l... 

There are no effective therapies for Alzheimer s disease and no cure. Treatment aims to enhance cholinergic transmission. The most useful drugs are central acetylcholinesterase inhibitors, for example donepezil. Acetylcholinesterase is the enzyme that normally breaks down acetylcholine after it has interacted with its receptors at the synapse. Inhibition of this enzyme in the brain increases the amount of acetylcholine available and prolongs its action. These drugs produce a modest improvement in memory or slow progression of symptoms in some patients. The response to anti-cholinesterase drugs may take several weeks. Their use is limited by side effects, which can be severe. 

Destruction or dissipation of the transmitter and termination of action. To sustain high frequency transmission and regulation of function, the synaptic dwell-time of the primary neurotransmitter must be relatively short. At cholinergic synapses involved in rapid neurotransmission, high and locahzed concentrations of acetylcholinesterase (AChE) are localized to hydrolyze ACh. When AChE is inhibited, removal of the transmitter occurs principally by diffusion, and the effects of ACh are potentiated and prolonged (see Chapter 8). 

The LD50 value in mice from intravenous administration of tabun has been reported as 0.287 mg/kg (Tripathi and Dewey 1989). Gupta and coworkers (1987) investigated acute toxicity of tabun and its biochemical consequences in the brain of rats. An acute nonlethal dose of 200 pg/kg was injected subcutaneously. Within 0.5-1 hour, the toxicity was maximal it persisted for 6 hours, accompanied by a sharp decline in acetylcholinesterase activity. The prolonged inhibition of this enzyme in muscle and brain may be due to storage aud delayed release of tabun from nonenzymic sites. In addition, cyanide released from a tabun molecule could cause further delay in recovery from its toxic effects. Atropine and its combination with various compounds may offer protection against tabun (see Sections 39.2 and 39.3). 

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