Cholinergic transmission cholinesterase inhibitors

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. 

At the neuromuscular junction, nicotinic function is enhanced by inhibition of AChE. However, unlike muscle nAChRs, some neuronal nAChRs, particularly those bearing the a7 subunit, recognize both acetylcholine and its metabolite choline as full agonists (Pereira et al., 2002). Therefore, cholinesterase inhibition may not necessarily enhance functions mediated by these nAChRs. In fact, cholinesterase inhibitors do not affect a7 nAChR-mediated synaptic transmission evoked by low-frequency stimulation of cholinergic fibers in chick cUiary ganglia (Zhang et al., 1996). 

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. 

Cholinesterase inhibitors increase the availability of acetylcholine at cholinergic synapses, resulting in increased transmission of acetylcholine by cholinergic neurons that have not been destroyed by the Alzheimer s disease. 

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