Synapse acetylcholinesterase inhibition

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

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. 

Indirect-acting stimulants increase activity at cholinergic synapses by inhibiting the acetylcholinesterase enzyme.21 This enzyme is normally responsible for destroying acetylcholine after this neurotransmitter... 

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. 

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... 

Tsukada H, Nishiyama S, Fukumoto D, Ohba H, Sato K, Kakiuchi T (2004) Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function functional imaging of the conscious monkey brain using animal PET in combination with microdialysis. Synapse 52 1-10. 

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). 

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. 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

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. 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

Exposure to disulfoton can result in inhibition of acetylcholinesterase activity, with consequent accumulation of acetylcholine at nerve synapses and ganglia leading to central nervous system, nicotinic, and muscarinic effects (see Section 2.2.1.4 for more extensive discussion). 

We noted above that too much acetylcholine in the synapse or at a neuromuscular junction can be a problem black widow spider venom works that way by causing massive release of this neurotransmitter. There is another way to accomplish the same thing inhibit the normal route by which acetylcholine once released is subsequently removed. That route is degradation by acetylcholinesterase, an enzyme that catalyzes... 

To avoid the undesirable effects of excess cholinergic stimulation, ACh is rapidly hydrolyzed after its release at the synapse by an enzyme named acetylcholinesterase AChE. A similar enzyme, butylcholinesterase BuChE also occurs. If the cholinesterase is inhibited, the ACh is not hydrolyzed so rapidly, and levels of ACh rise. 

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

Mechanism of Action A cholinesterase inhibitor that inhibits the enzyme acetylcholinesterase, thus increasing the concentration of acetylcholine at cholinergic synapses and enhancing cholinergic function in the CNS. Therapeutic Effect Slows the progression of Alzheimer s disease. 

Mechanism of Action A parasympathetic, anticholinesterase agent that inhibits destruction of acetylcholine by acetylcholinesterase, thus causing accumulation of acetylcholine at cholinergic synapses. Results in an increase in cholinergic responses such as miosis, increased tonus of intestinal and skeletal muscles, bronchial and ureteral constriction, bradycardia, and increased salivary and sweat gland secretions. Therapeutic Effect Diagnosis of myasthenia gravis. 

Diazinon toxicity results predominantly from the inhibition of acetylcholinesterase in the central and peripheral nervous system. The enzyme is responsible for terminating the action of the neurotransmitter, acetylcholine, in the synapse of the pre- and post-synaptic nerve endings or in the neuromuscular junction. However, the action of acetylcholine does not persist long as it is hydrolyzed by the enzyme, acetylcholinesterase, and rapidly removed. As an anticholinesterase organophosphate, diazinon inhibits acetylcholinesterase by reacting with the active site to form a stable phosphorylated complex which is incapable of destroying acetylcholine at the synaptic gutter between the pre- and post-synaptic nerve... 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

Many of the most effective insecticides available today are based on the same biochemical mechanism of the nerve gases— that is, the potent inhibition of the enzyme acetylcholinesterase. These chemicals are effective as insecticides because insects, who share our evolutionary history on this planet, are also vulnerable to having too much acetylcholine in their synapses. 

Unlike the systemic direct-acting cholinergic stimulants (e.g., bethanechol), cholinesterase inhibitors display a relative lack of specificity regarding which cholinergic synapses they stimulate. These drugs tend to inhibit the acetylcholinesterase found at... 

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