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Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophos...
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Context 1
... in various parts of the body, such as neuromuscular junctions in the peripheral nervous system (PNS), parasympathetic nervous system (PSNS), central nervous system (CNS) synapses, and linked to erythrocyte membranes in the blood, AChE plays a fundamental role in the neurosynaptic communication process (Figure 1) [18]. With a determining action in the finalization of the nerve impulse propagation, AChE is responsible for maintaining the appropriate levels of ACh ( Figure 2) [19]. AChE inactivates the action of ACh by hydrolyzing it into choline and acetate [20]. ...
Context 2
... inactivates the action of ACh by hydrolyzing it into choline and acetate [20]. With a determining action in the finalization of the nerve impulse propagation, AChE is responsible for maintaining the appropriate levels of ACh ( Figure 2) [19]. AChE inactivates the action of ACh by hydrolyzing it into choline and acetate [20]. ...
Citations
... This hypothesis proposes that the cognitive and memory deficits observed in AD are mostly caused by declined level of choline, particularly the neurotransmitter acetylcholine (ACh) in the brain, and restoring or maintaining ACh levels can alleviate these symptoms [32,33]. Therefore, the most effective treatment of AD involves increasing the levels of ACh at synapses by inhibiting the catalytic activity of acetylcholinesterase (AChE) [34]. The structure of AChE, as revealed by crystallography, is indicative of a deep gorge that measures 20 Å and encompasses two distinct binding sites -the catalytic active site (CAS) and the peripheral anionic site (PAS). ...
... In recent years, domestic and foreign studies have concentrated on the aging process and spontaneous reactivation of AChE in mammalians (e.g., mice, human blood, rabbits, zebrafish, etc.) inhibited by OPs [21][22][23]. Several important achievements with a significant reference value have been reported in these studies. However, the reports on insect-related research are relatively scarce, and none have been published comparing insect species for differences related to AChE. ...
Organophosphorus insecticides (OPs), acting as serine phosphorylating agents in acetylcholinesterase (AChE), are highly effective neurotoxic insecticides. In our previous research, we found that six herbivorous pests and four ladybirds howed significantly higher AChE LC50 values than seven parasitoids and a predator (Epistrophe balteate), and that there was a significant correlation with the corresponding bimolecular rate constant (Ki) value. The Ki value of pests was much smaller than that of natural enemies and had a higher LC50 value.Then, we speculated that the low sensitivity of the pest AChE to OPs may be associated with its higher recovery and lower aging ability. In this work, the I50 and I90 were calculated, to determine the sensibility of AChE in ten representative species, including Plutella xylostella, Prodenia litura, Musca domestica, and Cavia porcellus, to paraoxon and malaoxon. The enzyme activities were measured at various time points, and kinetic calculations were used to obtain their spontaneous reactivation (Ks) and aging (Ka) constants, which were comprehensively compared. We conclude that the Ka and Ks of the AChE inhibited by OPs showed primarily species-specific correlations, and little correlation with the sensitivity to OPs. The differences in the AChE sensitivity to paraoxon among the ten species were much greater than in the sensitivity to malaoxon. Compared to paraoxon, malaoxon was more selective for Cavia porcellus. Coleoptera insects showed a stronger dephosphorylation ability than other insect groups. The recovery ability of phospho-AChE was stronger in mammals than in insects, which could be related to the low sensitivity of the AChE site of action to OPs. The Ka of the AChE inhibited by malaoxon was larger than that inhibited by paraoxon with the corresponding biomaterials, indicating that the OP type had a substantial relationship with the Ka of the AChE. We further discovered that, when insects were inhibited by OP, the tendency of AChE to undergo aging was greater than that of dephosphorylation. Overall, the study provides valuable information on the action mechanism of various OPs on AChE in several species, which could be used to further research into AChE and the potential dangers that organophosphates pose to animals.
... The virtue has led to prove AChE activity test to be considered as biomarker for OP based chemical toxicity analysis. Moreover, the assay has been used as an reliable method for detection of CP toxicity in mammalian cells (de Castro et al., 2020). As shown in Fig. 5B, a concentrationdependent decrease in AChE activity was observed in zebrafish exposed to CP at a concentration range of 50 μg/ml to 500 μg/ml. ...
The extensive use of Chlorpyrifos (CP) as insecticide has raised concern to their hazardous impact on human health and ecosystems. Bioremediation has been proved as one of the key eco-compatible method for reducing these environmental toxicants. This study explores and evaluate the effectiveness of a combined process including solar Photo-Fenton process followed by bacterial degradation using Ochrobactrum sp. CPD-03 for effective CP degradation in wastewater. Moreover, the in vivo molecular biotoxicity of CP and degraded CP has been evaluated with embryonic zebrafish. The solar Photo-Fenton treatment showed CP degradation efficiency of ~42 % in 4 h and ~92 % in 96 h with combined bacterial degradation process. In vivo biotoxicity analysis showed increased survivability of embryonic zebrafish exposed to CP with CPD-03 in water with lesser morphological abnormalities. The mechanistic molecular analysis showed decreased acetylcholinesterase inhibition and GST activity in embryos exposed to CP with CPD-03 for a lesser apoptosis due to influential intrinsic interaction with metabolic proteins. The study advocated to the use of solar Photo-Fenton process followed by bacterial degradation for an efficient ecological degradation of CP for effective reduction of in vivo biotoxicity.
... In addition to the both drugs, diazepam can be applied to arrest seizures and convulsions (Ganie et al., 2022). Nowadays, novel reactivators of inhibited AChE, to reverse OP-mediated poisoning, are still under intensive development (de Castro et al., 2020). Additionally, novel methods for prevention and treatment of the Fig. 1. ...
This article reviews available data regarding the possible association of organophosphorus (OP) pesticides with neurological disorders such as dementia, attention deficit hyperactivity disorder, neurodevelopment, autism, cognitive development, Parkinson's disease and chronic organophosphate-induced neuropsychiatric disorder. These effects mainly develop after repeated (chronic) human exposure to low doses of OP. In addition, three well defined neurotoxic effects in humans caused by single doses of OP compounds are discussed. Those effects are the cholinergic syndrome, the intermediate syndrome and organophosphate-induced delayed polyneuropathy. Usually, the poisoning can be avoided by an improved administrative control, limited access to OP pesticides, efficient measures of personal protection and education of OP pesticide applicators and medical staff.
... Based on the structure of the standard monoquaternary and bisquaternary reactivators, novel oxime were prepared, e.g. derivatives of 2-PAM or group of reactivators called ,,Koximes" [14][15][16][17] . Some of the K-oximes showed promising results in restoring activity of AChE inhibited by several OPs. ...
The organophosphorus antidotes, so-called oximes, are able to restore the enzymatic function of acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) via cleavage of organophosphate from the active site of the phosphylated enzyme. In this work, the charged pyridinium oximes containing thiocarboxamide moiety were designed, prepared and tested. Their stability and pKa properties were found to be analogous to parent carboxamides (K027, K048 and K203). The inhibitory ability of thiocarboxamides was found in low µM levels for AChE and high µM levels for BChE. Their reactivation properties were screened on human recombinant AChE and BChE inhibited by nerve agent surrogates and paraoxon. One thiocarboxamide was able to effectively restore function of NEMP- and NEDPA-AChE, whereas two thiocarboxamides were able to reactivate BChE inhibited by all tested organophosphates. These results were confirmed by reactivation kinetics, where thiocarboxamides were proved to be effective, but less potent reactivators if compared to carboxamides.
... The current known organophosphates that are used as nerve poisons include sarin, cyclosarin, tabun, VX, Russian VX, Chinese VX, soman and novichok ( Figure 5) [47,48,49,50]. A detailed investigation on the OP poisoning and the development of AChE reactivators as antidotes appeared in the literature [51]. A recent literature review by Worek et al., focused on the area of OP poisoning and lists the systematic development of oxime reactivators to counter the toxic effects of OP derivatives [52]. ...
Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.
... central and peripheral effects which fall under the cholinergic syndrome spectra [9]. Nowadays, inhibition of AChE and BuChE have been a very crucial issue for pharmacological treatments of several disasters. ...
... 5,6 To address these problems, a large number of new potential reactivators were synthesized and need to be evaluated. 7 New candidate antidotes are screened using in vitro human-AChE based assays. Despite potential interspecies variability, it is imperative to use animal models to discover and evaluate the efficacy of medical countermeasures against OP poisoning. ...
Introduction:
Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, there are not universal antidotes able to reactivate AChE inhibited by any OP agent.
Areas covered:
This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like therapeutic and toxicological profile of these antidotes.
Expert opinion:
Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.
Background:
Acetylcholinesterase (AChE) regulates the transmission of neural messages by hydrolyzing acetylcholine in synaptic spaces.
Objective:
The effects of many AChE inhibitors have been evaluated in the treatment of Alzheimer's disease, but the present study examined a synthetic complex containing cobalt (SC) for the first time in the field of enzyme activity to evaluate enzyme inhibitory function.
Methods:
Ellman's test was applied. AChE function was assessed in the presence of SC through docking and molecular dynamics analyses. The second structure of AChE was studied through circular dichroism (CD) spectroscopy.
Results:
Several enzymatic methods were utilized for the kinetics of AChE, which indicated the non-Michaelis and positive homotropic behavior of AChE in the absence of inhibitors (Hill coefficient = 1.33). However, the existence of inhibitors did not eliminate this homotropic state, and even AChE had a more sigmoidal shape than the galantamine at the presence of SC. Based on the CD spectroscopy results, AChE structure changed in the existence of inhibitors and substrates. Bioinformatics analysis revealed SC bonding to the channel of active site AChE. The number of hydrogen bonds was such that the flexibility of the enzyme protein structure due to inhibitor binding reduced AChE function.
Conclusion:
The results reflected that AChE exhibited a non-Michaelis and positive homotropic behavior, leading to a more inhibitory effect on the SC than the galantamine. The positive homotropic behavior of AChE was intensified due to the alteration in AChE protein structure by binding SC to hydrophobic region in the active site pathway and impressing Trp84.
