Neurotoxicity acetylcholinesterase inhibition

Hoskins, B., Fernando, J.C., Dulaney, M.D. (1986). Relationship between the neurotoxicities of soman, sarin and tabun, and acetylcholinesterase inhibition. Toxicol. Lett. 30 121-9. 

Cholinesterase inhibition can sometimes persist for weeks thus, repeated exposures to small amounts of this material may result in accumulation of acetylcholinesterase inhibition with possible sudden-onset acute toxicity. Chlorpyrifos may be capable of causing organophosphate-induced delayed neurotoxicity in humans a massive overdose resulted in signs characteristic of delayed neurotoxicity. Animal studies generally indicate, however, that doses several times higher than the LD50 would be required to initiate delayed neurotoxicity. 

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. 

With repeated exposures, acetylcholinesterase inhibition can persist without indications of toxicity. In most cases, cholinesterase inhibition is without overt effects. Methyl parathion cannot cause delayed neurotoxicity. 

Pesticide assessment guidelines under the Federal Insecticide, Fungicide, and Rodenticide Act stipulate that organophosphates proposed for use as insecticides be tested both for their capability to cause acute toxicities due to inhibition of acetylcholinesterase and for their potential to cause inhibition of neurotoxic esterase and subsequent delayed neuropathy. Testing could be performed in laboratory rodents because they, like all species, are susceptible to acetylcholinesterase inhibition, but rodents do not develop notable ataxia, and neuropathological... 

Veronesi B, Pope C (1990) The neurotoxicity of parathion-induced acetylcholinesterase inhibition in neonatal rats. Neurotoxicology... 

Richardson, R. J., Moore, T.B., Kayyali, U.S., Fowke, J.H., and Randall, J.C. Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro. Application to assessment of neuropathic risk, Fundam. Appl. Toxicol. 20,273-279,1993. 

The inhibition of two cholinesterase activities in blood can also be used to confirm exposure to certain organophosphate ester compounds. Red blood cell acetylcholinesterase is the same cholinesterase found in the gray matter of the central nervous system and motor endplates of sympathetic ganglia. Synonyms for this enzyme include specific cholinesterase, true cholinesterase, and E-type cholinesterase. Plasma cholinesterase is a distinct enzyme found in intestinal mucosa, liver, plasma, and white matter of the central nervous system. Synonyms for this enzyme include nonspecific cholinesterase, pseudocholinesterase, butyrylcholinesterase, and S-type cholinesterase (Evans 1986). Nonspecific cholinesterase is thought to be a very poor indicator of neurotoxic effects. 

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]. 

Carbamates Organic chemical compounds that can be neurotoxic by competitively inhibiting acetylcholinesterase binding to acetylcholine. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Neurotoxic venoms of cobras, mambas, and coral snakes Inhibit the enzyme acetylcholinesterase. - This hydrolase normally breaks down the neurotransmitter acetylcholine within nerve synapses. 

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