AChEI activity

Some of these irreversible AChEI insecticides have a sulfur atom bonded to the phosphorus atom ith a coordinate-covalent bond. These compounds exhibit little AChEI activity, but they are rapidly bioactivated via desulfurization by microsomal oxidation in insects to afford the corresponding oxo derivatives (phosphate esters), hich are quite potent. A good example of this bioactivation phenomenon is illustrated by the commercially available insecticide parathion and its bioactivation to a toxic metabolite paraoxon. 

The biological activity of flavonoids has attracted much interest in the part twenty years and a few compounds of this class have been shown to have AChEI effects. The flavanone naringenin (74) from Citrus junos (Rutaceae) ameliorated scopolamine-induced amnesia in mice, which may be related to an antiAChE effect, since naringenin was shown to inhibit AChE in vitro dose dependently. A recent theoretical study has shown that flavonoids and xanthones exhibit polyvalent effects such as antioxidant, amyloid reduction and cholinesterase inhibition, which made them interesting candidates for further studies. 

Neuropathologically, AD is characterized by (1) parenchymal amyloid deposits or neuiitic plaques (2) intraneuronal deposits of neurofibrillary tangles (3) cerebral amyloid angiopathy, and (4) synaptic loss." Current treatment for AD in most countries consists in the administration of AChEIs to increase the amount of acetylcholine (ACh) at the neuronal synaptic cleft by inhibiting AChE, based on the finding that ACh is dramatically low in the brains of AD patients. AChE is an enzyme that breaks down ACh, a neurotransmitter in the brain that is required for normal brain activity and is critical in the process of forming memories. 

In vitro studies have demonstrated that ZT-1 is a potent and selective AChEI in rat cortex homogenate and in red blood cell AChE from different species (rat, bovine, and human). In contrast, ZT-1 presents a much weaker inhibitory activity on rat BuChE. In vitro, the AChE inhibitory effect of ZT-1 and HA is in the same range and slightly stronger than tacrine. 

Maximal AChE inhibition in rat whole brain was reached 1 hour after i.g. administration of ZT-1 (0.4 mg/kg), HA (0.4 mg/kg), donepezil (6.7 mg/kg), and tacrine (28.1 mg/kg). Significant inhibition in cortex AChE was observed between 0.5 and 3 hours with all four AChEIs. Significant inhibition was still present for ZT-1 and HA at 6 hours, but not for donepezil and tacrine. Peak inhibition of serum BuChE was almost comparable for ZT-1 (28%) and HA (34%), slightly more pronounced for donepezil (39%), and clearly greater for tacrine (65%). The BuChE activity returned to near control level 6 hours postadministration for ZT-1 or HA, whereas it was still partially inhibited for donepezil and especially tacrine. 

The phosphorothioates and phosphorodithioates, shown in Table 1 of Chapter 2, were developed when the nerve agents were found to be too toxic and volatile for use in agriculture. These OP insecticides contain a P-S-alkyl and/ or a P=S group in their structure. The best known member of this class is parathion, the most widely used insecticide at one time and responsible for more cases of accidental poisoning and death than any other OP compound. The activation and conversion of this weak AChEI (parathion) to the more active and potent form (paraoxon) was demonstrated to lake place in the liver (Diggle and Gage, 1951 Gage, 1953). 

AChEIs such as OPs and CMs have neuro- and myoioxic effects that destroy neurons and muscle fibers by exdioioxic actions, mediated by ACh receptor overstimulation following AChEI application, A rapid and significant increase in NO precedes increases in iipid peroxidation, mitochondrial dysfunction, loss of energy metabolites, as well as a reduction of COX activity, and an increase in xanthine oxidase. 

It is established (hat the coirelation between AChE inhibition (AChEI) in erythrocytes and that in the nervous system is usually unknown, and data on brain AChEI arc considered to be of greater value than those on erythrocytes in assessing the cholinergic effects of cholinesterases (ChEs). However, in the absence of measurements of brain AChE, those of erythrocyte AChE serve as a better indicator of toxicity than those of plasma ChE activity. In vitm kinetic studies may be necessary for pesticides with antiesterase activity. Results of these studies in different species may be combined with in vivo Study findings to establish ADls for these compounds. 

Donepezil is another "nonclassic," centrally acting, reversible, noncompetitive AChEI that was approved in 1997 for treatment of mild-to-moderate AD and dementia. Its selectivity for AChE is 570- to 1,250-fold that for butyrylcholinesterase, and it also exhibits greater affinity for brain AChE than for AChE in the periphery (47). When compared to tacrine, donepezil exhibits greater CNS AChE selectivity, longer elimination half-life (70-104 hours in subjects older than 55 years) and little or no potential for hepatotoxicity. Donepezil is metabolized by CYP2D6 and CYP3A4 via demethylation, debenzylation, hydroxylation, oxidation to the c/s-N-oxide, and glucuronidation. The 6-0-desmethyl metabolite accounts for 11 % of a dose, and it exhibits AChE inhibitory activity comparable to that of the parent compound. 

It appeared that cholinergic transmission performed other new functions. It can modulate various aspects of immune function, both innate and adaptive. Cholinergic transmission influences immune cell proliferation, cytokine production, differentiation of T-helper cells, and antigen presentation. These effects are mediated by cholinergic mAChR and nAQiR and other cholinergic components present in immune cells, for example, a7 nAQiR has the ability to induce anti-inflammatory activity [89]. This is probably one of the reasons why acetylcholinesterase inhibitors (AChEIs) act far broader than just to the inhibition of AChE. 

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