Anticholinesterase Compounds Research Articles

Naturally Occurring Cholinesterase Inhibitors from Plants, Fungi, Algae, and Animals: A Review of the Most Effective Inhibitors Reported in 2012-2022.

Since the development of the "cholinergic hypothesis" as an important therapeutic approach in the treatment of Alzheimer's disease (AD), the scientific community has made a remarkable effort to discover new and effective molecules with the ability to inhibit the enzyme acetylcholinesterase (AChE). The natural function of this enzyme is to catalyze the hydrolysis of the neurotransmitter acetylcholine in the brain. Thus, its inhibition increases the levels of this neurochemical and improves the cholinergic functions in patients with AD alleviating the symptoms of this neurological disorder. In recent years, attention has also been focused on the role of another enzyme, butyrylcholinesterase (BChE), mainly in the advanced stages of AD, transforming this enzyme into another target of interest in the search for new anticholinesterase agents. Over the past decades, Nature has proven to be a rich source of bioactive compounds relevant to the discovery of new molecules with potential applications in AD therapy. Bioprospecting of new cholinesterase inhibitors among natural products has led to the discovery of an important number of new AChE and BChE inhibitors that became potential lead compounds for the development of anti-AD drugs. This review summarizes a total of 260 active compounds from 142 studies which correspond to the most relevant (IC50 ≤ 15 μM) research work published during 2012-2022 on plant-derived anticholinesterase compounds, as well as several potent inhibitors obtained from other sources like fungi, algae, and animals.

In silico molecular docking and dynamic simulation of anti-cholinesterase compounds from the extract of Catunaregam spinosa for possible treatment of Alzheimer's disease

Alzheimer's disease (AD), is characterized by a progressive loss of cognitive abilities as well as behavioral symptoms including disorientation, trouble solving problems, personality and mood changes. Acetylcholinesterase (AChE) is a promising target for symptomatic improvement in AD due to its consistent and early cholinergic deficit. This research has investigated the potential compounds from Catunaregam spinosa as AChE inhibitors as a treatment option for AD, aiming to enhance cholinergic neurotransmission and alleviate cognitive decline. Tacrine, the FDA's first approved treatment for AD, is no longer in use due to its hepatotoxicity. Box-Behnken design (BBD) modelling was used to optimise the ultrasonic extraction of alkaloids from the dried fruits of C. spinosa. GC-MS analysis revealed the presence of ninety phytoconstituents in the extract. Among them, eighty-nine new phytoconstituents are reported in this plant fruit for the first time. Out of ninety phytoconstituents, eight phytoconstituents showed the best binding affinity against the AChE enzyme, i.e., PDB IDs 1GQR, 1QTI and 4PQE of AD targets using iGEMDOCK. The lead hits were tested for their drug-like properties and atomistic binding mechanisms using in silico ADMET prediction, LigPlot analysis, and molecular dynamics simulation. The results suggest four compounds such as 1,4,7,10,13,16-hexaoxacyclooctadecane; butanoic acid, 3-methyl-2-[(phenylmethoxy)imino]-, trime; butane-1,2,3,4-tetraol; and D-(+)-ribonic acid.gamma-lactone as potent inhibitors of AChE for the possible treatment of AD.

Death Due To 2, 4-DI-Ethyl Ester Poisoning –A Rarely Documented Compound in Clinical and Forensic Practice

Poisoning with Herbicides, Pesticides and Rodenticides etc. is very common nowadays especially in the northern parts of India due to their easy availability from market. Such compounds are available in the houses of farmers, persons dealing in agriculture sectors. Most of the time the cases of poisoning which are brought to our hospitals or are brought for autopsy in the mortuaries are of Organo phosphates, Organo chloro compounds or Aluminum Phosphide poisoning. In this case, we will discuss about the poisoning with a rarely documented compound 2, 4 Di Ethyl Ester which is a compound of Phenoxy acetic group. 2,4 Dichlorophenoxyacetic acid (2,4-D) is a selective herbicide used to kill broad leafed plants. The signs and symptoms of this compound mimics with anti-cholinesterase compounds which might be the reason for under reporting of this compound as a potential cause of poisoning. The role of preserving blood sample during post-mortem to look for myoglobin and creatine phsphokinase levels may be of help in giving opinion regarding cause of death in case of negative FSL's reports.

13C NMR-based dereplication using MixONat software to decipher potent anti-cholinesterase compounds in Mesua lepidota bark

A bio-assay guided fractionation strategy based on cholinesterase assay combined with 13C NMR-based dereplication was used to identify active metabolites from the bark of Mesua lepidota. Eight compounds were identified with the aid of the 13C NMR-based dereplication software, MixONat, i.e., sitosterol (1), stigmasterol (2), α-amyrin (3), friedelin (6), 3β-friedelinol (7), betulinic acid (9), lepidotol A (10) and lepidotol B (11). Further bio-assay guided isolation of active compounds afforded one xanthone, pyranojacareubin (12) and six coumarins; lepidotol A (10), lepidotol B (11), lepidotol E (13), lepidotin A (14), and lepidotin B (15), including a new Mammea coumarin, lepidotin C (16). All the metabolites showed strong to moderate butyrylcholinesterase (BChE) inhibition. Lepidotin B (15) exhibited the most potent inhibition towards BChE with a mix-mode inhibition profile and a Ki value of 1.03 µM. Molecular docking and molecular dynamics simulations have revealed that lepidotin B (15) forms stable interactions with key residues within five critical regions of BChE. These regions encompass residues Asp70 and Tyr332, the acyl hydrophobic pocket marked by Leu286, the catalytic triad represented by Ser198 and His438, the oxyanion hole (OH) constituted by Gly116 and Gly117, and the choline binding site featuring Trp82. To gauge the binding strength of lepidotin B (15) and to pinpoint pivotal residues at the binding interface, free energy calculations were conducted using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) approach. This analysis not only predicted a favourable binding affinity for lepidotin B (15) but also facilitated the identification of significant residues crucial for the binding interaction.

How Can Different Land Use Impact Aquatic Organisms? An Evaluation of Metabolic Alterations During Embryonic Development of Freshwater Fish, Rhamdia quelen

Chemical compounds used in agricultural activities are constantly leaching to water bodies where they can potentially cause damage to non-target organisms. In this study, we attempt to understand how the change in land use and exposure to xenobiotic substances may alter the metabolism and neurotoxicity during the development of native fish. Embryonic development of Rhamdia quelen was used as a quality indicator of two different aquatic environments, a stream considered impacted (Tormenta) and another reference (Manoel Gomes). The eggs were exposed to water collected from the reference and impacted streams during the development period (12h, 24h, 48h, and, 72h). Changes in the activity of energy metabolism enzymes (HK, PFK, LDH, CS, MDH) and the antioxidant defense system (CAT, GPX, GR, GST) were observed in animals exposed to impacted stream water. The entry of xenobiotic compounds into rivers through the leaching of chemical molecules existent in the soil causes activation of enzymes with a detoxification function. Furthermore, inhibition of cholinesterase enzyme activity indicates contamination by anticholinesterase compounds such as organophosphates and carbamates. Sites with constant use of these compounds can trigger harmful effects to organisms in the early stages of fish development and alter the body's metabolic and defense enzymatic activities.

Anticholinesterase Compounds from Endemic Prangos uechtritzii.

In this study, the anticholinesterase effects of the extracts and isolated compounds from the roots of endemic Prangos uechtritzii Boiss & Hausskn (Apiaceae) are reported. A novel polyacetylenic compound; (+)-8-O-methyloplopantriol A along with two known polyacetylenes; (-)-panaxynol, (+)-falcarindiol and fifteen known coumarin derivatives; umbelliferone, 6-formylumbelliferone, suberosin, 7-demethylsuberosin, (+)-ulopterol, tamarin, psoralen, imperatorin, (+)-oxypeucedanin, (+)-oxypeucedanin hydrate, (+)-oxypeucedanin methanolate, (+)-marmesin, (-)-prantschimgin, (+)-decursinol, and (-)-adicardin were isolated from the hexane (Pu-HE), chloroform (Pu-CE), and methanol (Pu-ME) extracts of P. uechtritzii roots. (-)-Panaxynol, (+)-falcarindiol, 6-formylumbelliferone, (+)-decursinol, and (-)-adicardin were obtained from the genus Prangos for the first time. (+)-8-O-Methyloplopantriol A inhibited both AChE (IC50 =194.5±5.8 μM) and BChE (IC50 =51.9±2.96 μM) enzymes. (+)-Falcarindiol, 6-formylumbelliferone, 7-demethylsuberosin, tamarin, and imperatorin also exhibited BChE-specific inhibitory activities (IC50 =27.88-93.86 μM). (+)-Falcarindiol (IC50 =27.88±0.91 μM) and imperatorin (IC50 =30.89±1.40 μM) as the most active components could be led compounds to develop new BChE inhibitors with further research against Alzheimer's disease.

Organophosphates pesticide poisoning: a peculiar case report

Background: Acute organophosphate (OP) intoxication occurs following the absorption through gastrointestinal or respiratory tract, skin and rarely by intramuscular or intravenous route; in most cases is the result of suicidal attempt. These anticholinesterase compounds cause an acute cholinergic syndrome (with decreased consciousness, respiratory failure), an intermediate syndrome after 2 or 3 days from exposure (that requires prolonged ventilation), and finally a delayed neuropathy. In most cases an acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death.

Use of poisoned baits against wildlife. A retrospective 17-year study in the natural environment of Extremadura (Spain)

This study reports the results obtained from toxicological analyses of different types of baits referred to the laboratory of the Toxicology Area (Faculty of Veterinary Medicine, Cáceres, Spain) over a 17-year period (2002–2018). These baits were suspicious materials found in the environment of the region of Extremadura (Western Spain), where such malpractices are a problem to be addressed, as wide livestock farming and hunting activities are combined with a significant wealth of wildlife (especially birds of prey). A total of 246 baits, including 32 commercial chemical products to be used in baits, were analysed. Samples from 183 cases were received and classified according to the material used for their preparation and the toxic substance found. Overall, the most common bait consisted of meat preparations (56.3% of cases) intended to eliminate predators considered ‘annoying’ for livestock and hunting practices, such as carnivores and scavengers. It should be noted that contact baits (as fenthion-impregnated perches) were also detected (7.6%). Regarding the substances detected, anticholinesterase compounds (organophosphates and carbamates) were the most commonly used substances for the preparation of baits (detected in 85.3% of positive baits). Moreover, 8% of the positive baits presented more than one toxic substance in their composition. Due to the types of toxic compounds and the methods used to prepare the baits, this study shows that the malicious use of highly toxic substances in the environment to kill wildlife is a common and current issue and poses a serious risk to different species.

Assessment of the serum glucose/potassium GLU/K ratio as a predictor of intermediate syndrome following acute anticholinesterase exposure

BackgroundThe widespread use of anticholinesterase-containing pesticides accounts for the considerable morbidity and mortality in Egypt and worldwide. AimFew studies have investigated the predictors of intermediate syndrome (IMS). Therefore, in this study, we assessed the adequacy of the serum glucose/potassium (GLU/K) ratio as an early reliable tool to predict IMS incidence following intoxication with acute anticholinesterase compounds. MethodsA prospective cross-sectional study was conducted among patients who presented to Tanta University Poison Control Center, Egypt, and were diagnosed with acute anticholinesterase intoxication between January and August, 2021. Patients were categorized based on the primary outcome into IMS (+) and IMS (−) groups. ResultsOverall, 243 patients were included, among whom 44 (18.1%) had IMS as the complication. Younger individuals with age ranging between 18 and < 25 years constituted the main exposed age category in both groups. Vomiting and abdominal colic were the most commonly noted complaints in the included patients (94.2% and 63.8% of patients, respectively). The delay, length of hospital stay, mean blood pressure, O2 saturation, Glasgow Coma Scale score, random blood glucose level, K concentration, GLU/K ratio, and dose of atropine administered were significant IMS predictors on an individual basis, and the GLU/K ratio was the most significant IMS predictor. At a cutoff value of > 41.07%, the GLU/K ratio could significantly predict IMS (areas under the curves = 0.971, p < 0.001) with 93% accuracy, 93.2% sensitivity, and 93% specificity. ConclusionAlthough the clear pathophysiology of IMS remains to be elucidated, our results provide insight into the significant contribution of neurological affection, apart from the well-known direct toxic effect on muscles. Moreover, we demonstrated a significant association between the development of IMS and severity of organophosphorus compounds’ exposure. Physicians should be vigilant to detect IMS early upon admission using the GLU/K ratio, which is a useful early IMS predictor.

Anti-cholinergic activities of Turkish Corydalis DC. species

The aim of the present study is to determine the in vitro cholinesterase inhibitory effects of the tubers of Corydalis DC. species growing in Turkey belonging to Papaveraceae family. This genus comprises of approximately 470 species distributed in the world and is represented 17 species and 22 taxons, 8 of which are endemic, in the flora of Turkey. Some Corydalis species are used in folk medicine for the memory enhancement in Europe and China. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the ethanolic extracts prepared from tubers collected from 54 populations are screened by the slightly modified spectrophotometric method. The highest anticholinesterase compound/s were determined by assay-guided fractionation and their structures were elucidated through chromatographic (LC-Q-ToF-MS) and extensive spectroscopic techniques. According to the results, canadine, berberine and dehydrocorydaline from protoberberine-type isoquinoline alkaloids were exerted the most potent inhibitory effect against two enzymes. This is the first study determining anticholinesterase compounds of Corydalis species growing in Turkey.

Clock/Sleep-Dependent Learning and Memory in Male 3xTg-AD Mice at Advanced Disease Stages and Extrinsic Effects of Huprine X and the Novel Multitarget Agent AVCRI104P3.

A new hypothesis highlights sleep-dependent learning/memory consolidation and regards the sleep-wake cycle as a modulator of β-amyloid and tau Alzheimer’s disease (AD) pathologies. Sundowning behavior is a common neuropsychiatric symptom (NPS) associated with dementia. Sleep fragmentation resulting from disturbances in sleep and circadian rhythms in AD may have important consequences on memory processes and exacerbate the other AD-NPS. The present work studied the effect of training time schedules on 12-month-old male 3xTg-AD mice modeling advanced disease stages. Their performance in two paradigms of the Morris water maze for spatial-reference and visual-perceptual learning and memory were found impaired at midday, after 4 h of non-active phase. In contrast, early-morning trained littermates, slowing down from their active phase, exhibited better performance and used goal-directed strategies and non-search navigation described for normal aging. The novel multitarget anticholinesterasic compound AVCRI104P3 (0.6 µmol·kg−1, 21 days i.p.) exerted stronger cognitive benefits than its in vitro equipotent dose of AChEI huprine X (0.12 μmol·kg−1, 21 days i.p.). Both compounds showed streamlined drug effectiveness, independently of the schedule. Their effects on anxiety-like behaviors were moderate. The results open a question of how time schedules modulate the capacity to respond to task demands and to assess/elucidate new drug effectiveness.

Phytochemical isolation and biological screening of Cotoneaster microphyllus

ABSTRACT The root and aerial parts of Cotoneaster microphyllus were subjected to extraction and isolation of phytochemicals. The extracts were evaluated for their antioxidant anthelmintic, antimicrobial, and anticholinesterase potentials using standard protocols. Crude extract of aerial parts and roots, more potently scavenged DPPH free radicals with IC50 values of 83 and 66 μg/mL while ABTS with 92 and 90 μg/mL respectively. Chloroform fraction exhibited highest anthelmintic activity followed by ethyl acetate fraction. Ethyl acetate fraction produced high zone of inhibition against selected bacterial and fungal strains. Maximum phenolic contents and vitamin C were found in the ethyl-acetate and chloroform fractions and were therefore, biologically the most potent fractions. Ethyl acetate fraction exhibited highest anticholinesterase potential and was therefore subjected to silica gel column chromatography which resulted in the isolation of one new (1) and four known (2–5) compounds. The isolated compounds were also screened for anticholinesterase potentials. Compound 3, most potently inhibited acetyl cholinesterase and butyryl cholinesterase with IC50 value of 66 and 114 μg/mL, respectively. The extracts exhibited antioxidant, anticholinesterase, anthelmintic and antimicrobial potentials that should be further subjected for the isolation of other responsible compounds in pure state. As anticholinesterase compound 3 is a good candidate to be tested in animal models.

Counteracting poisoning with chemical warfare nerve agents.

Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.

Changes in anticholinesterase, antioxidant activities and related bioactive compounds of carob pulp (Ceratonia siliqua L.) during ripening stages

In the current study, in vitro neuroprotective effect of carob (Ceratonia siliqua L.) pulp (wild and cultivated varieties) at the unripe and ripe stage was investigated through testing against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), linked to Alzheimer’s disease (AD). As neurodegenerative disorders are strongly related to oxidative damage and metal accumulation, the antioxidant activity of carob extracts was determined by DPPH, ABTS, ferric reducing power (FRP), CUPRAC and ferrous iron chelating (FIC) assays at both ripening stages. Total phenolic (TPC), total flavonoids (TFC) and total condensed tannin contents (CTC) were also assessed. At the unripe stage, the samples of both varieties exhibited an interesting inhibitory effect against AChE and BChE with a strong antioxidant activity by scavenging free radicals and by acting as reducing agents. The result showed that the concentrations of TPC, TFC, and CTC were decreased significantly (P < 0.05) during ripening. The same observations were found for antioxidant activities. The results suggested that the extract of unripe carob may provide a substantial source of secondary metabolites, which act as natural antioxidants and as acetylcholinesterase inhibitors that may be beneficial in the treatment of AD.

The Cholinergic Anti-Inflammatory Pathway. Combined Effect of Anticholinesterase Compounds and its Antidote Cholinesterase Reactivator Carboxim

The Cholinergic Anti-Inflammatory Pathway. Combined Effect of Anticholinesterase Compounds and its Antidote Cholinesterase Reactivator Carboxim

The combined effect of anticholinesterase compound DDVP and its antidote cholinesterase reactivator carboxim on implementation of cholinergic anti-inflammatory pathway

The combined effect of anticholinesterase compound DDVP and its antidote cholinesterase reactivator carboxim on implementation of cholinergic anti-inflammatory pathway

Molecular Docking Studies of Coumarins Isolated from Extracts and Essential Oils of Zosima absinthifolia Link as Potential Inhibitors for Alzheimer's Disease.

Coumarins and essential oils are the major components of the Apiaceae family and the Zosima genus. The present study reports anticholinesterase and antioxidant activities of extracts and essential oils from aerial parts, roots, flowers, fruits and coumarins—bergapten (1); imperatorin (2), pimpinellin (3) and umbelliferone (4)—isolated of the roots from Zosima absinthifolia. The investigation by light and scanning electron microscopy of the structures of secretory canals found different chemical compositions in the various types of secretory canals which present in the aerial parts, fruits and flowers. The canals, present in the aerial parts, are characterized by terpene hydrocarbons, while the secretory canals of roots, flowers and fruits include esters. Novel data of a comparative study on essential oils constituents of aerial parts, roots, flowers and fruits of Z. absinthfolia has been presented. The roots and fruits extract showed a high content of total phenolics and antioxidant activity. The GC-FID and GC-MS analysis revealed that the main components of the aerial parts, roots, flowers and fruits extracts were octanol (8.8%), octyl octanoate (7.6%), octyl acetate (7.3%); trans-pinocarvyl acetate (26.7%), β-pinene (8.9%); octyl acetate (19.9%), trans-p-menth-2-en-1-ol (4.6%); octyl acetate (81.6%), and (Z)-4-octenyl acetate (5.1%). The dichloromethane fraction of fruit and flower essential oil was characterized by the highest phenolics level and antioxidant activity. The dichloromethane fraction of fruit had the best inhibition against butyrylcholinesterase enzyme (82.27 ± 1.97%) which was higher then acetylcholinesterase inhibition (61.09 ± 4.46%) of umbelliferone. This study shows that the flowers and fruit of Z. absinthifolia can be a new potential resource of natural antioxidant and anticholinesterase compounds.

ACTIVIDAD ACETILCOLINESTERASA (AChE) Y BUTIRILCOLINESTERASA (BUChE) EN POBLACIONES MEXICANAS: ESTUDIO PILOTO

La determinacion de las actividades acetilcolinesterasa (AChE) y butirilcolinesterasa (BuChE) es ampliamente utilizada en estudios de monitoreo biologico para evaluar la exposicion a compuestos anticolinesterasicos y sus efectos. No obstante, se ha observado una amplia variabilidad en los valores considerados como normales para estas actividades enzimaticas, lo que puede deberse a diversos factores. Uno de los que puede tener mas influencia es la falta de parametros preanaliticos y analiticos estandarizados. En este sentido, el objetivo de este trabajo fue conocer, con una metodologia consensuada, los intervalos de las actividades AChE y BuChE en individuos no expuestos ocupacionalmente a compuestos anticolinesterasicos en diferentes estados de la republica mexicana. Se observo que el 22 % de los laboratorios participantes reportaron valores de actividad AChE dentro del rango considerado como normal. Respecto a la actividad BuChE, el 67 % reporto valores dentro del rango para una poblacion no expuesta a compuestos anticolinesterasicos. Los resultados revelaron una importante variabilidad en los valores de las actividades AChE y BuChE, que muestran la necesidad de capacitacion continua entre los analistas y la homogeneizacion de las metodologias.

Huprine X Attenuates The Neurotoxicity Induced by Kainic Acid, Especially Brain Inflammation.

Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models invivo and invitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In this study, we assessed the ability of HX (0.8mg/kg, 21days) to prevent the damage induced by kainic acid (KA; 28mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain. KA administration significantly modified the levels of pAkt1, Bcl2, pGSK3β, p25/p35, increased the glial cell markers and reduced the neurogenesis process. We also observed that pre-treatment with HX significantly reduced the p25/p35 ratio and increased synaptophysin levels, which suggests a protective effect against apoptosis and an improvement of neuroplasticity. The increase in GFAP (88%) and Iba-1 (72%) induced by KA was totally prevented by HX pre-treatment, underlying a relevant anti-inflammatory action of the anticholinesterasic drug. Our findings highlight the potential of HX, in particular, and of AChEIs, in general, to treat a number of diseases that course with both cognitive deficits and chronic inflammatory processes.

THE PROBLEM OF THE INTERMEDIATE SYNDROME FOLLOWING POISONING WITH ANTI-CHOLINESTERASE AGENTS

Etiology and pathogenesis current concepts of the intermediate syndrome in cases of poisoning with anticholinesterase compounds (organophosphorus compounds, carbamates) are considered in the review. Characteristics of the syndrome clinical picture and its diagnostics methods using electromyography are presented.. Data on the experience of broadly used basic antidotal agents (cholinesterase reactivators, M – and N-cholinoreceptors) and pathogenic therapy of poisonings were analyzed and summarized. To solve the problem, priority research directions were determined, such as search for formation mechanisms of the nondepolarizing neuromuscular blocker and development of methods for prophylaxis and therapy using drugs targeting N-cholinoreceptors.