Cholinesterase Activity Research Articles

Identification of neurotherapeutic constituents in Ocimum gratissimum with cholinesterase and mono amine oxidase inhibitory activities, using GC-MS analysis, in vitro, and in silico approaches

Neuroprotective activities of various extracts of Ocimum gratissimum (OG), have been reported, but there is paucity of information on its neurotherapeutic constituents. This study is aimed at identifying the neurotherapeutic constituents in OG leaves using in vitro assays, GC-MS chemical investigation and in silico studies including molecular docking, ensemble-based docking, molecular dynamics (MD) simulation, clustering and ADMET filtering analysis. Methanol extract of O gratissimum (MEOG) and solvent-partition (n-hexane, ethylacetate, and methanol residue fraction) of MEOG were investigated for in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) inhibition at concentration of 0.65, 12.5, 2.5, 5, and 10 mg/mL, using donepezil, phenazine methosulfate and selegiline as reference inhibitors for AChE, BChE and MAO B respectively. n-hexane solvent partition fraction was further investigated using GC-MS analysis. Identified compounds were screened against human AChE, BChE and MAO-B activities using molecular docking and molecular dynamics. The lead phytochemicals were further analysed for ADMET in silico analysis. MEOG and the 3 fractions (n-hexane, ethylacetate, and methanol residue fraction) inhibited the activities of AChE, BChE and MAO-B in a concentration-dependent manner with AChE (IC50 = 2.380, 2.022, 2.066 and 1.079 mg/mL respectively), BChE (IC50 = 2.261, 2.126, 2.630 and 1.465 mg/mL respectively) and MAO-B (IC50 = 2.345, 1.584, 2.933 and 2.935 mg/mL respectively). From the 38 GC-MS identified compounds, 7 hit compounds were further subjected to ensemble-docking, the lead phytochemicals (LP): cholestane and 3-methoxy-morphanin presented highest multiple binding tendencies to the three enzymes. Cholestane had the highest binding energies of −9.9, −9.0 and −11 kcal/mol, while 3-methoxy-morphanin presented the second-best binding energies of −9.3, −8.2 and −10.1 kcal/mol respectively. When compared with the binding pattern of reference inhibitors of the enzyme, lead phytochemicals were orientated in the catalytic sites of the enzyme and interacted with important catalytic residues. The LP-enzyme complexes were stable during the MD simulation analysis. Cholestane and 3-methoxy-morphanin presented favorable ADMET properties over several molecular descriptors and filters, with druggable properties and ability to cross the blood-brain barrier. Hence, cholestane and 3-methoxy-morphanin, in part, or in synergy with other hit phytochemicals, may be responsible for the neurotherapeutic activities of MEOG leaves.

Assessment of Cholinesterase inhibition activity of birds inhabiting pesticide exposed croplands and protected area in hot semi-arid region of Pakistan.

Acetylcholinesterase (AChE) activity levels can be used as an indicator for AChE inhibition due to pesticide poisoning in bird species. We assessed the comparative brain cholinesterase (AChE) activity level of five bird species inhabiting pesticide exposed croplands and Protected Area i.e. Deva Vatala National Park (DVNP), Bhimber by using a spectrophotometric method. AChE activity levels ranged from 56.3 to 85.9 µmol/min/g of brain tissue of birds representing DVNP. However, AChE activity levels ranged from 27.6 to 79.9 µmol/min/g of brain tissue of birds representing croplands. AChE activity levels observed in Jungle babbler, Common babbler, and Red-vented bulbul showed significant differences (P < 0.05) at two sites. However, White wagtail and Black drongo demonstrated non-significant differences (P > 0.05). Maximum inhibition was recorded in Jungle babbler (53%) followed by Common babbler (35%), Red-vented bulbul (18%), White wagtail (15%), and Black drongo (7%). The brain cholinesterase inhibition levels under-protected ecosystems (DVNP, Bhimber) and agricultural landscape suggest insecticidal contamination and its impact on avifauna diversity. The study also emphasizes on the importance of pesticide-free zones to protect the biodiversity of birds.

Fenugreek seed powder protects mice against arsenic-induced neurobehavioral changes

The current study was designed to evaluate the protective effect of fenugreek seed powder against As-induced neurobehavioral and biochemical perturbations using a mouse model. Mice exposed to arsenic at 10 mg/kg body weight showed development of anxiety-like behavior and memory impairment compared to control mice in elevated plus maze and Morris water maze tests, respectively. A significantly decreased acetyl and butyrylcholinesterase, superoxide dismutase and glutathione reductase activities and brain-derived neurotrophic factor levels were found in the brain of arsenic-exposed mice compared to control mice. Interestingly, supplementation of fenugreek seed powder to arsenic-treated mice significantly restored the activity of cholinesterase and antioxidant enzymes (e.g. superoxide dismutase, glutathione reductase) as well as brain-derived neurotrophic factor levels in the brain tissue of arsenic-exposed mice. Consequently, reduced anxiety-like behavior, improved learning and memory were observed in fenugreek supplemented arsenic treated mice compared to only arsenic-exposed mice group. Thus, this study suggests that fenugreek seed powder reduces arsenic-induced neurotoxicity in mice.

Association of Serum Cholinesterase and Liver Enzymes with Clinical Severity and Outcomes in Organophosphorus Poisoning

Abstract Background: Organophosphorus (OP) compound poisoning is a medico-toxic emergency that results in multiorgan failure. The primary mechanism of action is by inhibition of acetylcholinesterase, leading to disruption in processes of oxidative stress, apoptosis, and microsomal metabolism resulting in liver toxicity. The present study was conducted to explore the prognostic value of serum cholinesterase in predicting severity of organophosphorous compound poisoning and the need for ventilatory support; and to understand the role of aspartate aminotransaminase (AST), alanine aminotransaminase (ALT) and bilirubin in assessing the severity of acute organophosphate poisoning. Methodology: Hospital-based prospective observational study was conducted among OP poisoning cases at a tertiary hospital in Hubli. Clinical examination was done during the initial resuscitation and treatment of patients. Three milliliter of plain blood was collected on admission before administration of atropine and plasma cholinesterase level, and other biochemical parameters were estimated. Results: Sixty-five percent of poisoning cases had &gt;50% of cholinesterase activity with normal grade poisoning. Moderate and severe grade poisonings were present among 3% and 5% of poisoning cases, respectively. Patients with cholinesterase level activity of ≤50% had significantly higher proportions of respiratory failure (77%) and fatal outcomes (33%). Median levels of AST (Q2: 73.2 IU/mL) and ALT were significantly higher (Q2: 22.7 IU/L) among severe grade poisoning (Che: &lt;10%) compared to other grades of poisoning. Conclusion: The assessment of cholinesterase level activity in OP poisoning would be a useful guide to the physician for planning of intensive care, duration of hospital stay, and clinical prognosis. Serum AST and ALT levels can also contribute as supportive biomarkers to assess the severity, chances of respiratory failure, and clinical outcomes of OP poisoning.

Impacts of Dietary Chrysophyllum albidum Fruit Pulp on Brain Cholinesterase Function in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Epidemiologic studies have shown strong correlations between Alzheimer’s disease and diabetes mellitus. The exact mechanism through which this happens remains unclear. However, the dependence on glucose for brain function has been proposed as one possible mechanism. Hence, this study investigated the neuroprotective potential of Chrysophyllum albidum fruit pulp (CAPP) with hypoglycaemic properties in diabetic rats induced with high-fat diet/streptozotocin (STZ). The animals were grouped into seven units as follows: control, STZ-induced, STZ + metformin (positive control), STZ + 5% CAPP, STZ + 10% CAPP, control + 5% CAPP and control + 10% CAPP and each group was made up of six rats. The animals were first placed on normal diet (non-diabetic groups) and high fat diet (diabetic groups) for a fortnight, respectively before induction with STZ and were treated with diets containing 5 and 10% CAPP for 14 days. After the experiment, the rat brain cholinesterase and antioxidant activities were determined. The results revealed that acetylcholinesterase (AChE), butylcholinesterase (BuChE), arginase, adenosine deaminase (ADA) and antioxidant activities were altered in STZ-diabetic group in comparison to the control. However, a significant decrease at p &lt; 0.05 was found in the activities of AChE, BuChE, arginase and ADA. In addition, there was a concomitant rise in the levels of antioxidant in all the groups administered supplemented diets and the group treated with metformin in comparison to the STZ-diabetic group. Conclusively, we can suggest that the fruit pulp prevents neurological damage in diabetic rats via anticholinesterase activity and improvement of brain antioxidant status.

A novel RP-HPLC method for quantification of cholinesterase activity in human blood: An application for assessing organophosphate and carbamate insecticide exposure.

Several methods have been reported to estimate Acetylcholinesterase (AChE) enzyme activity in blood samples. The Ellman assay is the most important among all but with several shortcomings, and there is a need to develop a method which is accurate, sensitive and quick for analyzing AChE. Therefore, we have developed an assay utilizing RP-HPLC with UV detection for the determination of AChE activity. This method measured the conversion of 1-naphthol acetate to 1-naphthol to estimate AChE activity in blood samples. Performance was judged on the basis of reproducibility, sensitivity, accuracy, and the ability to screen enzyme activity within 20minutes. A series of experiments were performed, varying the concentration of blood and substrate, with optimal sensitivity using 50 μM substrate and 10μL blood. The validation parameters such as linearity (R2 of ≥ 0.9842 for 1-naphthol and ≥ 0.9897 for 1-naphthol acetate), precision (94.21-96.41%), accuracy (85.2%-99.6% and 82.6%-99.3% for 1-naphthol and 1-naphthol acetate respectively), and robustness were validated according to International Conference on Harmonization (ICH) guidelines. Blood samples were collected from healthy people, farmers exposed to spraying of pesticides, and suicidal patients who ingested pesticides and were hospitalized and were analyzed by the developed method. The AChE level was approximately 21 units/mL compared to 24units/mL in controls, whereas suicidal patients showed the least AChE levels of 1 unit/mL. The employment of this method is recommended for estimating AChE level on various matrices.

Blood cholinesterase activities and oxidative stress status among farmworkers using pesticides in Duhok, KRG, Iraq

Background: The use of pesticides by farmworkers poses considerable health risks. This study was undertaken to examine plasma and erythrocyte cholinesterase activities, plasma oxidative biomarkers malondialdehyde (MDA), and total antioxidant status (TAS) among farmworkers using different pesticide products in Duhok, northern of Iraq. Methods: This is a case-control study conducted between November 2021 to July 2022 on 92 male farmworkers who were exposed to pesticides in comparison with 44 non-exposed male subjects (control). The availability and uses of pesticides were obtained from 19 agrochemical shops and the farmworkers exposed to pesticides. Demographic data of pesticide-exposed farmworkers and their practice of pesticide applications were recorded. Plasma and erythrocyte cholinesterase activities and plasma MDA and TAS levels were determined in both groups. Results: The farmworkers had a significant 10.0% increase in plasma MDA level, with no significant changes in blood cholinesterase activities or the TAS level. Odds and risk ratios of reduced plasma cholinesterase activity (20.0%) suggested an association of health risks in pesticide-exposed farmworkers. Most of the pesticide products (278) in use were insecticides (47.0%), which comprised mainly 26.0% pyrethroids and 3.0-7.0% anticholinesterase insecticides, among others. The majority of the farmworkers (51%) were merely aware of the general target use of the pesticide, and 75% had an exposure history of &gt; 5 years. Pesticide application was mostly (50.0%) manual, and 54.0% used insufficient personal protection equipment; 32.0% ate and drank at work, 48.0% practiced disposal of empty pesticide containers by burning and/or burying them, whereas 25.0% dumped the containers indiscriminately, and 25% disposed them at garbage sites openly. Conclusion: The farmworkers, with only a marginal increase in oxidative stress biomarker MDA, did not suffer from significant reductions in blood cholinesterase activities, although odds and risk ratios of reduced plasma cholinesterase activity suggested a health risk. Implementation of a national program is needed to measure pre-exposure blood cholinesterase activities in farmworkers.

Target Organ Toxicity in Rats After Subchronic Oral Exposure to Soil Extracts Containing a Complex Mixture of Contaminants.

Complex mixtures of unknown contaminants present a challenge to identify toxicological risks without using large numbers of animals and labor-intensive screens of all organs. This study examined soil extracts from a legacy-contaminated pesticide packaging and blending site. HepG2 cytotoxicity was used as an initial screen of 18 soil samples; then, three extracts (A, B and C) from different locations at the study site were used for testing in animals. The first two extracts were identified as the most toxic in vitro, and the latter extract obtained from a location further from these two toxic sampling sites. Then, target organ toxicities were identified following biweekly oral gavage for one month of three soil extracts (0.1% in polyethylene glycol or PEG) compared to vehicle control in male Sprague-Dawley rats (n = 9-10/group). Exposure to extract A significantly increased neutrophils and lymphocytes compared to control. In contrast, all extracts increased plasma α-2 macroglobulin and caused mild-to-moderate lymphocytic proliferation within the spleen white pulp, all indicative of inflammation. Rats exposed to all soil extracts exhibited acute tubular necrosis. Cholinesterase activity was significantly reduced in plasma, but not brain, after exposure to extract A compared to control. Increased hepatic ethoxyresorufin-o-deethylase activity compared to control was observed following exposure to extracts A and B. Exposure to soil extract C in rats showed a prolonged QTc interval in electrocardiography as well as increased brain lipid peroxidation. Candidate contaminants are organochlorine, organophosphate/carbamate pesticides or metabolites. Overall, HepG2 cytotoxicity did not successfully predict the neurotoxicity and cardiotoxicity observed with extract C but was more successful with suspected hydrocarbon toxicities in extracts A and B. Caution should be taken when extrapolating the observation of no effects from in vitro cell culture to in vivo toxicity, and better cell culture lines or assays should be explored.

Pseudo-irreversible butyrylcholinesterase inhibitors: Structure–activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead

Alongside reversible butyrylcholinesterase inhibitors, a plethora of covalent butyrylcholinesterase inhibitors have been reported in the literature, typically pseudo-irreversible carbamates. For these latter, however, most cases lack full confirmation of their covalent mode of action. Additionally, the available reports regarding the structure–activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors and the structure–activity relationships of the N-dialkyl O-arylcarbamate warhead are presented in this study. The covalent mechanism of binding was tested by IC50 time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic analysis. Computational studies provided valuable insights into steric constraints and identified problematic, bulky carbamate warheads that cannot reach and carbamoylate the catalytic Ser198. Quantum mechanical calculations provided further evidence that steric effects appear to be a key factor in determining the covalent binding behaviour of these carbamate cholinesterase inhibitors and their duration of action. Additionally, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatisation with azide-containing fluorophore enabled fluorescent labelling of plasma human butyrylcholinesterase. This proof-of-concept study highlights the potential of this novel approach and for these compounds to be further developed as clickable molecular probes for investigating tissue localisation and activity of cholinesterases.

Clerodendrum viscosum leaves attenuate lead-induced neurotoxicity through upregulation of BDNF-Akt-Nrf2 pathway in mice

Ethnopharmacological relevanceClerodendrum viscosum is an important medicinal plant in Ayurveda in Bangladesh and its leaves are used as a remedy for various diseases such as anti-inflammatory, antibacterial, hyperglycemic, hepatoprotective effects. Aim of the studyThe present study aimed to evaluate the protective effect of aqueous extract of C. viscosum leaves against Pb-induced neurobehavioral and biochemical changes in mice. Materials and methodsSwiss albino mice were divided as a) control, b) lead treated (Pb) and c) C. viscosum leaves (Cle) d) Pb plus Cle groups. Pb-acetate (10 mg/kg body weight) was given to Pb and Pb + Cle groups mice, and water extract of leaves (50 mg/kg body weight) was provided as supplementation to Cle and Pb + Cle groups mice for 30 days. Elevated plus maze and Morris water maze tests were used for evaluating anxiety, spatial memory and learning, respectively. Status of cholinesterase, SOD, GSH enzyme activity and neurotoxicity markers such BDNF and Nrf2 levels were analyzed in the brain tissue of experimental mice. ResultsPoorer learning, inferior spatial memory, and increased anxiety-like behavior in Pb-exposure mice were noted when compared to control mice in Morris water maze and elevated plus maze test, respectively. In addition, expression of BDNF and Nrf2, cholinesterase activity along with antioxidant activity were significantly reduced compared to control group (p < 0.01). Interestingly, C. viscosum leaves’ aqueous extract supplementation in Pb-exposed mice provide a significant improved neurochemical and antioxidant properties through the augmentation of activity of cholinergic enzymes, and upregulation of BDNF and Nrf2 levels in the brain tissue compared to Pb-exposed mice. ConclusionsThis study suggested that C. viscosum leaves restore the cognitive dysfunction and reduce anxiety-like behavior through upregulation of BDNF mediated Akt-Nrf2 pathway in Pb-exposure mice.

Clinical Evaluation of Plasma Cholinesterase with Clinical Symptomatology in Organophosphorus Poisoning

Objective: Level of plasma cholinesterase and its association with clinical manifestations. Methods: This is a prospective study and observation study of 50 cases of organo phosphorus poisoning compound admitted in casualty and intensive care department. In present study we were evaluated plasma cholinesterase levels and correlate with clinical symptomatology in organo phosphorus poisoning, also included patient requiring ventilator support in respiratory failure patients. Prior approval for the study and the protocol was obtained from the institution ethical committee. In present study, serum cholinesterase estimation was repeated on after 6 hours, 12 hours, 24 hours, 48 hours, 96 hours and 7th day of stay in intensive care unit. The serum cholinesterase activity was measured by Genx cholinesterase butyryl thiocholinemethod (quantitative determination of cholinesterase in human serum). Conclusion: In present study 50 cases of organophosphorus compound poisoning admitted to our tertiary care centre. Commonest age group 21 to 30 years and 31 to 40 years. Serum cholinesterase is a useful marker for predicting clinical outcome in op poisoning as marked reductions are associated with increased need for ventilator support, atropine requirement, duration of hospital stay and outcome. Serum cholinesterase levels correlated well with clinical manifestation, severity of poisoning, ventilator support required or not and outcome.

Recognition and Assessment of Antidotal Effects of Diphenhydramine against Acute Carbaryl Insecticide Poisoning in a Chick Model

Diphenhydramine antagonizes poisoning produced by cholinesterase (ChE) inhibiting insecticides. This study examines the effects of diphenhydramine against acute poisoning induced by the carbamate insecticide carbaryl in a chick model. The effects of diphenhydramine on the 24 h median Lethal Dose (LD50), and acute toxicity of carbaryl were assessed in chicks (7-15 days old). The plasma and whole brain ChE activities were measured electrometrically in vitro and in vivo. Diphenhydramine at 10mg/Kg Body wt. administered intramuscularly 15 min before carbaryl dosing increased the oral LD50 value of carbaryl (207 mg/Kg Body wt.) by 62%. Carbaryl at 250 mg/Kg Body wt. has orally produced toxidrome of cholinergic poisoning with 100% lethality in 24 h. Diphenhydramine (10mg/ Kg Body wt.) used 15 min before carbaryl (250mg/Kg Body wt., orally) was the most effective dose (vs 5 and 20mg/Kg Body wt.) in delaying carbaryl-toxicity and increasing survivals in chicks. The intramuscular median effective dose (ED50) of diphenhydramine which prevented 24 h carbaryl-death in chicks was 8.6mg/ Kg Body wt. The antidotal response to diphenhydramine was similar to that of the standard antidote atropine sulfate. Diphenhydramine at 10mg/Kg Body wt., given immediately after carbaryl (200mg/Kg Body wt.), reduced the percentages of plasma and whole brain ChE inhibitions in vivo by 12- and 13%, respectively. Carbaryl (10μmol/L) in vitro inhibited ChE activities in the plasma and brain by 53 and 77%, respectively; these inhibitions were reduced by 13- and 14%, respectively, when diphenhydramine (10μmol/L) was added to in vitro reactions. Diphenhydramine exerted antidotal action against a model of acute and lethal carbaryl intoxication in chicks.

Subchronic toxicity of oral deltamethrin in laying chickens.

Pyrethroid pesticides, with low toxicity to birds and mammals and short persistence in the environment, are widely used now. With the development of intensive poultry farming, pesticide application leads to residues in poultry products and pollution in ecological environment. The aim of the present study was to examine deltamethrin subchronic toxicity in laying chickens. One hundred and twelve laying chickens were randomly assigned to 14 groups including 13 groups medicated with deltamethrin (n = 8) and one unmedicated group used as control (n = 8). Tissue samples were collected during and after administration for weighing and histopathological analysis. A single dose of deltamethrin (20 mg·kg-1·BW·d) was administered orally to laying chickens for 14 days. The results showed that deltamethrin has no significant effect on the relative organ weight of laying chickens (p > 0.05). The activities of aspartate aminotransferase and cholinesterase in the plasma gradually decreased over time in the medicated group (p < 0.05). Plasma concentrations of urea nitrogen, uric acid, cholesterol, triglycerides, and creatinine significantly increased during treatment (p < 0.05), and significant liver damage and loss of intestinal villous epithelium were observed. The intestinal wall thickness, villus height, and crypt depth of laying chickens were altered by deltamethrin treatment. During treatment was withdrawn, the intestinal repair was more extensive than the liver repair.

Influence of pyrrolizidine alkaloids depletion upon the biological activity of Symphytum officinale L. extracts

Ethnopharmacological relevanceComfrey (Symphytum officinale L., Boraginaceae) root preparations are used as both traditional remedies and therapeutic agents in treating pain and inflammation associated with joint, bone, and muscle ailments. Even though numerous phytochemicals contribute to the beneficial effects of comfrey, the presence of toxic pyrrolizidine alkaloids (PAs) overshadows its uses. Aim of the studyIn this work, different PA-/mucilage-depleted/undepleted comfrey root extracts were subjected to detailed phytochemical characterization and biological evaluation. Materials and methodsThe phytochemical profiling was performed by LC-HRMS/MS. The quantification of PAs and major phenolic compounds was carried out by LC-MS/MS and LC-DAD. Antioxidant and enzyme inhibitory activity was determined by in vitro free radical scavenging, ion reducing, metal chelating, cholinesterase, tyrosinase, amylase, and glucosidase assays. Using an ex vivo model of LPS-stimulated neutrophils, their viability (as measured by flow cytometry) and the release of IL-1β, IL-8, and TNF-α were determined (ELISA assay). Results12 phenolic acids, six PAs, three organic acids, two fatty acids, and two sugars were identified in the obtained comfrey extracts. The PA-depleted materials contained PAs levels below 2 ppm, whereas the removal of mucilage increased the content of rosmarinic acid, globoidnan A, globoidnan B, and rabdosiin. PA-depletion did not significantly affect the antioxidant potential. However, the radical scavenging and metal reducing properties were higher in the mucilage-depleted extracts. Neither PA-depletion nor mucilage-depletion had considerable effects on the in vitro inhibitory activity of cholinesterases, tyrosinase, amylase, and glucosidase or release of ex vivo pro-inflammatory cytokines (e.g., IL-1β, IL-8, and TNF-α) in LPS-stimulated neutrophils. ConclusionsIn light of their superior safety profiles, PA-depleted comfrey extracts can be utilized further in cosmetic and pharmaceutical products.

Association between cholinesterase activity and critical illness brain dysfunction

BackgroundDelirium is a frequent manifestation of acute brain dysfunction and is associated with cognitive impairment. The hypothesized mechanism of brain dysfunction during critical illness is centered on neuroinflammation, regulated in part by the cholinergic system. Point-of-care serum cholinesterase enzyme activity measurements serve as a real-time index of cholinergic activity. We hypothesized that cholinesterase activity during critical illness would be associated with delirium in the intensive care unit (ICU) and cognitive impairment after discharge.MethodsWe enrolled adults with respiratory failure and/or shock and measured plasma acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity on days 1, 3, 5, and 7 after enrollment. AChE values were also normalized per gram of hemoglobin (AChE/Hgb). We assessed for coma and delirium twice daily using the Richmond Agitation Sedation Scale and the Confusion Assessment Method for the ICU to evaluate daily mental status (delirium, coma, normal) and days alive without delirium or coma. Cognitive impairment, disability, and health-related quality of life were assessed at up to 6 months post-discharge. We used multivariable regression to determine whether AChE, AChE/Hgb, and BChE activity were associated with outcomes after adjusting for relevant covariates.ResultsWe included 272 critically ill patients who were a median (IQR) age 56 (39–67) years and had a median Sequential Organ Failure Assessment score at enrollment of 8 (5–11). Higher daily AChE levels were associated with increased odds of being delirious versus normal mental status on the same day (Odds Ratio [95% Confidence Interval] 1.64 [1.11, 2.43]; P = 0.045). AChE/Hgb and BChE activity levels were not associated with delirious mental status. Lower enrollment BChE was associated with fewer days alive without delirium or coma (P = 0.048). AChE, AChE/Hgb, and BChE levels were not significantly associated with cognitive impairment, disability, or quality of life after discharge.ConclusionCholinesterase activity during critical illness is associated with delirium but not with outcomes after discharge, findings that may reflect mechanisms of acute brain organ dysfunction.Trial Registration: NCT03098472. Registered 31 March 2017.

The significance of thymoquinone administration on liver toxicity of diazinon and cholinesterase activity; a recommendation for prophylaxis among individuals at risk

BackgroundDiazinon (DZN), a widely used chemical herbicide for controlling agricultural pests, is an important organophosphorus pesticide and an environmental pollutant which induces toxic effects on living organisms during long-term exposure. Thymoquinone (TQ) is a phytochemical bioactive compound with antioxidant and anti-inflammatory properties. We aimed to evaluate the protective effects of TQ against DZN-induced hepatotoxicity through alleviating oxidative stress and enhancing cholinesterase (ChE) enzyme activity.MethodsRats were randomly divided into six groups (n = 8); a negative control group receiving corn oil; a group only receiving DZN (20 mg/kg/day); a group treated with TQ (10 mg/kg/day), and three treatment groups as TQ + DZN, receiving different doses of TQ (2.5, 5, and 10 mg/kg/day). All experimental animals were orally treated for 28 consecutive days. The levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactic acid dehydrogenase (LDH) were determined. In addition, ChE activity and histopathological changes were evaluated.ResultsThe results showed that DZN decreased GSH level (p < 0.01) and SOD activity (p < 0.01) in parallel to an increase in MDA level (p < 0.01) and increased the activity of AST, ALT, ALP, and LDH (p < 0.01) in comparison to the negative control group. Our findings demonstrated that TQ administration could diminish hepatotoxicity and reduce oxidative damage in DZN-treated rats, which could be linked to its antioxidant and free radical scavenging properties. It was also observed that TQ 10 mg/kg remarkably increased the activity of acetylcholinesterase, butyrylcholinesterase, and SOD enzymes, elevated GSH, decreased MDA, and reduced pathological alternations of the liver induced by DZN.ConclusionThymoquinone 10 mg/kg increased the activity of plasma and blood cholinesterases and reduced DZN-induced alternations of the liver. Improvement of butyryl- and acetylcholinesterase activity suggests that maybe TQ supplement could be beneficial as pre-exposure prophylaxis among farm workers spraying pesticides.

Is there Cholinesterase Activity in the Eye?

The nervous system regulates the visual system through neurotransmitters that play an important role in visual and ocular functions. One of those neurotransmitters is acetylcholine, a key molecule that plays a variety of biological functions. Moreover, acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine, is implicated in cholinergic function. However, several studies have demonstrated that in addition to their enzymatic functions, acetylcholinesterase exerts non-catalytic functions. In recent years, the importance of evaluating all possible functions of acetylcholine-acetylcholinesterase has been shown. Nevertheless, there is evidence suggesting that cholinesterase activity in the eye can regulate some biological events both in structures of the anterior and posterior segment of the eye and, therefore, in the visual information that is processed in the visual cortex. Hence, the evaluation of cholinesterase activity could be a possible marker of alterations in cholinergic activity in both ocular and systemic diseases.

From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders.

A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H2O2-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.

Evaluation of Toxic Effects Induced by Sub-Acute Exposure to Low Doses of α-Cypermethrin in Adult Male Rats.

To contribute new information to the pyrethroid pesticide α-cypermethrin toxicity profile, we evaluated its effects after oral administration to Wistar rats at daily doses of 2.186, 0.015, 0.157, and 0.786 mg/kg bw for 28 days. Evaluations were performed using markers of oxidative stress, cholinesterase (ChE) activities, and levels of primary DNA damage in plasma/whole blood and liver, kidney, and brain tissue. Consecutive exposure to α-cypermethrin affected the kidney, liver, and brain weight of rats. A significant increase in concentration of the thiobarbituric acid reactive species was observed in the brain, accompanied by a significant increase in glutathione peroxidase (GPx) activity. An increase in GPx activity was also observed in the liver of all α-cypermethrin-treated groups, while GPx activity in the blood was significantly lower than in controls. A decrease in ChE activities was observed in the kidney and liver. Treatment with α-cypermethrin induced DNA damage in the studied cell types at almost all of the applied doses, indicating the highest susceptibility in the brain. The present study showed that, even at very low doses, exposure to α-cypermethrin exerts genotoxic effects and sets in motion the antioxidative mechanisms of cell defense, indicating the potential hazards posed by this insecticide.

Biochemical and Behavioural Alterations Induced by Arsenic and Temperature in Hediste diversicolor of Different Growth Stages

Contamination with Arsenic, a toxic metalloid, is increasing in the marine environment. Additionally, global warming can alter metalloids toxicity. Polychaetes are key species in marine environments. By mobilizing sediments, they play vital roles in nutrient and element (including contaminants) cycles. Most studies with marine invertebrates focus on the effects of metalloids on either adults or larvae. Here, we bring information on the effects of temperature increase and arsenic contamination on the polychaete Hediste diversicolor in different growth stages and water temperatures. Feeding activity and biochemical responses-cholinesterase activity, indicators of cell damage, antioxidant and biotransformation enzymes and metabolic capacity-were evaluated. Temperature rise combined with As imposed alterations on feeding activity and biochemical endpoints at different growth stages. Small organisms have their antioxidant enzymes increased, avoiding lipid damage. However, larger organisms are the most affected class due to the inhibition of superoxide dismutase, which results in protein damage. Oxidative damage was observed on smaller and larger organisms exposed to As and temperature of 21 °C, demonstrating higher sensibility to the combination of temperature rise and As. The observed alterations may have ecological consequences, affecting the cycle of nutrients, sediment oxygenation and the food chain that depends on the bioturbation of this polychaete.