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In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer’s Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aβ) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 μM and after 48 h the maintenance temperature was increased to 25 ° C for Aβ expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aβ toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aβ aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.

Essential oil (EO) was hydrodistilled from Achillea biebersteinii and analyzed using gas chromatography–flame ionization detection (GC–FID) and (GC–MS). Three monoterpenes, α-terpinene, p-cymene, and camphor were isolated as the main terpenes in the EO. Oil-in-water nanoemulsion (particle size 52.7 ± 4.4 nm) was prepared and characterized from EO through a hydrothermal approach. The EO products caused insecticidal effects and altered F1 progeny of the red flour beetle, Tribolium castaneum (Herbst) in a dose and exposure time-dependent manner. The nanoemulsion was superior in bioactivity, followed EO. At 12.5 µl/cm2, nanoemulsion and EO caused 100% mortality of the second larvae after 4 days of exposure with reduction of F1 progeny of 100.0 and 89.2%, respectively. At 50.0 µl/cm2, percentage mortality and reduction in progeny of EO products ranged between (61.4–100%) and (53.0–100%), respectively. Upon fumigation, nanoemulsion at 10 µl/L air caused 100% mortality of the second larvae after 4 days of exposure. At 20 µl/L air and 4 days after treatment, percentage mortality with the remainder botanicals ranging between 64.7 and 100. LC50′s of products after 48 h exposure ranging between 6.7 and 58.1 µg/cm2 in insecticidal bioassay, and between 3.6 and 26.3 µl/L upon fumigation. Botanicals caused a remarkable inhibition of acetylcholinesterase activity (AChE), where nanoemulsion (IC50 = 14.22 mM), EO (IC50 = 35.12 mM) and camphor (IC50 = 23.93 mM) were superior as AChE inhibitors. There is a potential for using of A. biebersteinii EO, its nanoemulsion and monoterpenes as natural grain protectants after the required toxicological investigations.

© 2021 SAABEthanolic extracts prepared from forty-seven macroalgae species collected from the Mediterranean Sea, Aegean Sea, and Sea of Marmara were tested at 200 μg/mL against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase (TYR), crucial for insect vivacity. Only one alga extract, e.g. Dictyota dichotoma var. intricata (C.Agardh) Greville 1830, had a notable inhibition of BChE (72.0 ± 0.07%), whereas the rest of the macroalgae possessed no or low inhibition of AChE (2.20 ± 0.39% - 14.20 ± 2.16%), BChE (0.62 ± 0.07% - 41.20 ± 3.07%), and TYR (< 10%). Several known diterpenes (isoamijiol, 14-deoxyamijiol, amijidictyol, dictyodial, and 4α-acetoxydictyodial) found earlier in this species were proceeded to molecular docking experiments to figure out its interactions with BChE. Eleven of the 47 macroalgal extracts were selected based on sufficient availability for testing in larvicidal and adulticidal activity assays against female Aedes aegypti “Orlando1952” the mosquito vector of yellow fever and dengue. The selected extracts displayed a high adulticidal activity ranging between 80–100% activity at 5 μg/mosquito. In contrast, only the ethanol extract of Ceramium siliquosumvar. elegans showed larvicidal mortality of 93.3 ± 11.5% at 0.5 μg/mL. Our findings show that the macroalgae and their metabolites could be sources of novel insecticidal agents.

Rutin (RUT) is a biologically active flavonoid that is reported to modulate radiation-induced brain dysfunctions. However, RUT's poor water solubility and low brain bioavailability limit its clinical use. To increase its brain bioavailability, RUT was loaded onto nanoplatforms based on chitosan/diacrylated pluronic (CS/DA-PLUR) nanogels synthesized by gamma radiation. The optimized formulation was investigated as a carrier system for RUT. Based on pilot experiments' results, the cranial radiation (CR) dose that induced cognitive dysfunction was selected. In the main experiment, rats were pre-treated orally with either free RUT or RUT-CS/DA-PLUR. Rats' cognitive and motor functions were assessed; 24 h later, rats were sacrificed, and the whole brain was separated for histopathological examination and biochemical estimation of brain content of acetylcholine esterase (AChE), neurotransmitters, oxidative stress markers, and interleukin-1β. CR produced prominent impairment in spatial and non-spatial learning memory, motor coordination, and muscular strength. Moreover, histopathological and biochemical alterations in brain contents of neurotransmitters, oxidative stress, and interleukin-1β were induced by CR. Conversely, RUT-CS/DA-PLUR, but not free RUT, successfully guarded against all the detrimental effects induced by CR. Based on the current findings, loading of RUT enhanced its bioavailability and therapeutic effectiveness by restoring the cognitive functions impaired by CR.

The AChE inhibitory activity of alkaloid extracts and compounds has been in the focus of research on the plants of Amaryllidoideae subfamily since the approval of galanthamine in 2001 by FDA for treatment of mild to moderate Alzheimer's disease. A small fraction of the huge biodiversity of the plants producing Amaryllidaceae alkaloids has been studied as a source of AChE inhibitors. Less than 20% of the known Amaryllidaceae alkaloids have been tested in vitro for their ability to inhibit AChE. Galanthamine, lycorine and haemanthamine are scaffolds for semi-synthesis of potent AChE inhibitors. In the last years, galanthamine has been studied in silico for drug optimization and synthesis of potent dual-binding AChE inhibitors. In silico studies of other Amaryllidaceae alkaloids have also provoked the interest of researchers in the last years. The aim of this article is to provide a comprehensive review on studies of the AChE inhibitory activity of extracts and compounds from the plants of Amaryllidoideae subfamily covering the literature from the last two decades.

The use of acetylcholinesterase (AChE) inhibitors, antioxidants or multitarget compounds are among the main strategies against Alzheimer’s disease (AD). Between AChE inhibitors, those targeting the peripheral anionic site (PAS) are of special interest. Here, we describe the rational design and synthesis of peptide analogs of a natural PAS-targeting sequence that we recently discovered, aiming at increasing its activity against AChE. We also tested their radical scavenging and metal chelating properties. Our design strategy was based on the position-specific, computer-aided insertion of aromatic residues. The analog named as W3 showed a 30-fold higher inhibitory activity than the original sequence and an improved antioxidant activity. W3 is the most potent modified natural peptide against Electrophorus electricus AChE ever reported with an IC50 of 10.42 μM (± 1.02). In addition, it showed a radical scavenging activity of 47.00% ± 3.11 at 50 μM and 93.47% ± 1.53 at 400 μM. Since peptides are receiving increasing interest as drugs, we propose the W3 analog as an attractive sequence for the development of new peptide-based multitarget drugs for AD. Besides, this work sheds light on the importance of the aromatic residues in the modulation of AChE activity and their effect on the radical scavenging activity of a peptide.

The analgesic, antidiarrheal, and neuro-pharmacological potentials of Medicago denticulata leaves extract were screened in animal models. Potential analgesic response was noted (*P

Cannabis is an annual herbaceous plant sometimes grown for decoration and used as bird food that looks like flax. The study wanted to determine if a Cannabis extract may have an effect on how anxious and depressed the female mice behaved. forty healthy female mice were divided into four groups. Tap water was administered to the first group (control). Ethanol was administered to second group (positive control). The third and four groups were given 1 and 2 mg/kg cannabis extract respectively. Treatment continued for 14 days. After therapy, the light–dark chamber, forced swimming, tail suspension, plus lamb and open field tests were done to assess anxiety and depressive behavior. The results indicated that the anxiety and depression were increased in treated females significantly compared to control. Biochemical results showed that DA,5-HT, AChE, GSH, GST, CAT and SOD were decreased while TBARS, corticosterone and cortisol were increased. In conclusion, cannabis effects this kind of females’ behavior but the mechanisms are not clear yet. We need more researches on this trend.

Alzheimer’s disease (AD) is one of the most common forms of dementia and is associated with a decline in cognitive function and language ability. The deficiency of the cholinergic neurotransmitter known as acetylcholine (ACh) is associated with AD. Acetylcholinesterase (AChE) hydrolyses ACh and inhibits the cholinergic transmission. Furthermore, both AChE and butyrylcholinesterase (BChE) plays important roles in early and late stages of AD. Therefore, the inhibition of either or both cholinesterase enzymes represent a promising therapeutic route for treating AD. In this study, a large-scale classification structure–activity relationship model was developed to predict cholinesterase inhibitory activities as well as revealing important substructures governing their activities. Herein, a non-redundant dataset constituting 985 and 1056 compounds for AChE and BChE, respectively, was obtained from the ChEMBL database. These inhibitors were described by 12 sets of molecular fingerprints and predictive models were developed using the random forest algorithm. Evaluation of the model performance by means of Matthews correlation coefficient and consideration of the model’s interpretability indicated that the SubstructureCount fingerprint was the most robust with five-fold cross-validated MCC of [0.76, 0.82] for AChE and BChE, respectively, and test MCC of [0.73, 0.97]. Feature interpretation revealed that the aromatic ring system, heterocyclic nitrogen containing compounds and amines are important for cholinesterase inhibition. Finally, the model was deployed as a publicly available webserver called the ABCpred at http://codes.bio/abcpred/ .

Hypothyroidism has been reported to be associated with cognitive decline. Considering the role of folic acid (FA) in cognitive performance, the present study was designed to investigate the effects of FA on hypothyroidism-induced cognitive impairment, oxidative damage, and alterations in acetylcholinesterase (AChE) activity in rat model of propylthiouracil (PTU)-induced hypothyroidism. In this study, PTU (0.05% in drinking water) and FA (5, 10, and 15 mg/kg, oral gavage) were administered for the rats during 7 weeks. Then, behavioral performance was tested using Morris water maze (MWM) and passive avoidance (PA) tasks. Finally, oxidative stress indicators and AChE activity were assayed in the brain tissues. The impairing effect of hypothyroidism on cognitive performance was markedly alleviated by FA especially at higher doses. In the MWM test, FA reduced escape latency and travelled distance, compared to the non-treated hypothyroid group. In the PA test, latency to enter dark chamber was significantly enhanced by FA compared to the non-treated hypothyroid group (p

Backround: Celery (Apium graveolens L., Apiaceae) is one of the medicinal plants with secondary metabolite components that have pharmacological effects such as vitamin (choline) content. This study aims to evaluate the mechanism and interaction of choline contained in celery on its effectiveness as a neuroprotective. Methods: This research is an experimental research using the in silico study. Results: The insilico search found that the choline content in celery binds to Slc5a7, Chat and Ache. Which has a function in the process of neurotransmitter biosynthesis, neurotransmitter metabolic processes and neurotransmitter secretion processes Conclusion: The celery (Apium graveolens L., Apiaceae) have pharmacological activity as neuroprotective through the interaction of Slc5a7, Chat and Ache

Chlorpyrifos (CPF), an organophosphorous pesticide, can be found in aquatic ecosystems at concentrations of up to several hundred nanograms per liter because of water runoff from treated crops. While some studies have shown that low concentrations of CPF may have adverse effects on aquatic species, comparatively little is known about its effect on fish embryos and larvae. To investigate the developmental effects of CPF, rainbow trout (Oncorhynchus mykiss) eyed-stage embryos were exposed in semistatic conditions to 0.3 and 3 µg/L of CPF up to the end of the sac-fry stage, 3 weeks, at 12 °C. Several endpoints were analyzed including survival, hatching delay, hatching success, biometry, swimming activity, DNA damage, lipid peroxidation, protein carbonyl content, acetylcholinesterase (AChE) activity, and gene expression. At the end of the 3-week exposure, larvae exposed to the highest concentration of CPF were less mobile compared to the control and the lowest CPF conditions. No significant differences in AChE activity were observed in either set of CPF conditions compared to control, but it was significantly reduced for larvae exposed to 3 µg/L compared to those exposed to 0.3 µg/L of CPF. Expression of genes that encoded estrogen receptor beta was downregulated for larvae exposed to both CPF concentrations. Expression of cytochrome P450 family 19 subfamily A member 1 was also significantly repressed but only on larvae exposed to the highest concentration of CPF. Our results indicated that subchronic exposure to environmental concentrations of CPF could lead to sublethal effects on early-life stages of rainbow trout, especially effects on swimming activity that could affect foraging activity and escaping from predators. Environ Toxicol Chem 2021;40:3092-3102. © 2021 SETAC.

Background: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients. Objective: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively. Methods: The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM). Results: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE’s active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6). Conclusion: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC50 values of 0.285–100 µM compared to butyrylcholinesterase (BChE) with IC50 values of > 100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC50 value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against H2O2-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer’s disease. A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285–100 μM) compared to butyrylcholinesterase (BChE) with IC50 values of > 100 μM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c′] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC50 value of 0.285 μM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

Stomach horse bots (Gasterophilus intestinalis larvae; Diptera: Oestridae) are obligatory parasites inhabit the stomach of domestic Equidae. Colonization of Gasterophilus intestinalis larvae cause funnel-shaped stomach ulcers, sub-serosal abscess, and peritonitis. In the current research work, 3rd instar larvae of G. intestinalis were exposed to different concentrations (5, 10, 20, 40, 80 and 100 ppm) of curcumin from turmeric plant root (Curcuma longa). Survival of insect larvae, their morphological characterization, growth regulation, enzymatic assay and comet assay were assessed. Curcumin exhibited time and concentration dependent insecticidal effect on survival of 3rd instar larvae of G. intestinalis (bot flies). The aqueous extract of curcumin was highly toxic to G. intestinalis larvae with LC50 value of 16.92 ppm after 24 h. The mean comet tail length (µm) and tail moment (µm) at the highest curcumin concentration of 100 ppm were 16.03 ± 0.15 and 3.03 ± 0.09 µm, whereas DNA damage percent was 14.77 ± 0.12%. Further, remarkable inhibition of Glutathione S-transferases (GST) and Acetylcholinesterase (AChE) enzymatic activity were detected. Aqueous extract of curcumin exhibited potent lethal effects to the 3rd instar larvae of G. intestinalis, therefore, it could be used as an active and harmless natural insecticidal to control bot flies’ larvae in donkeys.

The impact of two organophosphorus insecticides [Chlorpyrifos (CPF) and Monocrotophos (MCP)] on non-target wild natural gastropod, Pila globosa (apple snail) from the paddy fields was studied. The activity of acetylcholinesterase (AChE) was monitored on foot-muscle and hepatopancreas tissues of control and exposed snails. In the foot- muscle AChE inhibition progressed and reached 54.19% and 63.13% of the control, whereas, the AChE inhibition in the hepatopancreas reached 46.96% and 53.67% over control after 48 hours of exposure to 1.5 mL.L-1 and 2.5 mL.L-1 CPF respectively. After 48 hours of MCP exposure at 1.5 mL.L-1 and 2.5 mL.L-1 separately, the AChE inhibition of foot muscle was 49.07% and 57.59% respectively while in hepatopancreas it was 44.65% and 48.84% respectively. Our results show more inhibition of AChE activities on the foot-muscle than hepatopancreas in a concentration and time-dependent manner with greater severity by CPF in comparison to MCP. AChE inhibition increased with the increasing exposure time.

Palladium/BuAd2P efficiently catalyzed the direct α-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue (12) shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. Docking results of compound 12 also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).

Acute toxicity of organophosphorus compounds is primarily caused by inhibition of acetylcholinesterase (AChE) at cholinergic synapses. The current study was designed to investigate the effects of paraoxon on histological changes as well as the role of mitochondrion-dependent apoptosis in causing this damage in the rat cerebellum. Adult male Wistar rats were intraperitoneally injected with paraoxon at 0.3, 0.7, or 1 mg/kg. Control animals were injected with corn oil as a vehicle. At 14 or 28 days after intoxication, histological changes and alterations in the expression of apoptosis-related proteins, including Bax, Bcl-2, and caspase-3, were investigated in the cerebellum using cresyl violet staining and western blotting, respectively. Findings showed the decreased thickness of both molecular and granular layers and reduction in the number of Purkinje cells in animals treated with a higher convulsive dose of paraoxon (1 mg/kg). In addition, exposure of rats to 1 mg/kg of paraoxon activated apoptosis pathway confirmed by an increase in Bax and caspase-3 and a decrease in Bcl-2 protein levels. According to our results, cerebellar histological changes and alterations in the expression of apoptosis-related proteins occur following exposure to a high convulsive dose of paraoxon and persist for a long time.

The aim of this study is to assess the toxicity of ibuprofen (IBU) and propranolol (PRO) drugs usingGammarus pulex as a model organism. Firstly, the 96 h LC50 values of IBU and PRO were determined and then three sublethal concentrations of the drugs were exposed to G. pulex. The activities of superoxide dismutase (SOD), catalase (CAT) and acetylcholinesterase (AChE) were evaluated. SOD activity decreased in G. pulex exposed to IBU and PRO compared to control. In all groups exposed to IBU, CAT activity increased at different concentrations at 24 and 96 h. In the groups exposed to different PRO concentrations, CAT activities increased after 24 h compared to the control group (p < 0.05). AChE activities increased in all application groups exposed to IBU for 96 hours (p < 0.05). In conclusion, exposure to IBU and PRO resulted in increased oxidative damage. PRO has been found to cause neurotoxicity.

Introduction: Low back ache constitute a group of symptoms with no clear etiopathogenesis and pose a major difficulty for a health care professional to diagnose and treat the disease per se. Low back ache has become permanent disability for certain individuals and interferes with normal functioning of day-to-day life activities. Objective: This study was undertaken to establish the correlation and functional outcome between combination of Vitamin D & magnesium supplementation and Vitamin D supplementation for patients with non-specific low back ache. Materials and Methods: An observational comparative study was performed with 117 patients of nonspecific low back ache from June 2019 to May 2020. Out of 117 patients, a total of 60 patients (Group A) were treated with a combination of Vitamin D supplementation along with magnesium tablets for 3 consecutive months and remaining 57 patients (Group B) were treated with Vitamin D supplementation for 3 consecutive months. Both the groups were followed up for 6 months for pain relief assessed by VAS score and functional improvement in quality of life assessed by Oswestry Low Back Pain Disability Questionnaire. Results: A significant difference was noted in the Group A compared to Group B which demonstrates an additive effect on the combination used in them. When analysing the change in parameters compared to the pre-interventions state both the groups showed significant improvements. However, upon analysis of the correlation between the parameters with regard to the change among the groups, we noted that Group A showed significant correlation with respect to the Calcium and Vit-D level improvement out of the intervention upon the observed results. Conclusion: Treatment of non-specific low back ache with vitamin-D and magnesium shows synergistic effects with significant improvement in the functional outcomes and the pre-intervention metabolic parameters. Keywords: Vitamin D, Magnesium, Low back ache, Spi

The free radicals produced by cigarette smoking are responsible for tissue damage, heart and lung diseases, and carcinogenesis. The effect of tobacco on the central nervous system (CNS) has received increased attention nowadays in research. Therefore, to explore the molecular interaction of cigarette smoke carcinogens (CSC) 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK), and N′-nitrosonornicotine (NNN) with well-known targets of CNS-related disorders, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes, a cascade of the computational study was conducted including molecular docking and molecular dynamics simulations (MDS). The investigated results of NNAL+AChEcomplex, NNK+AChEcomplex, and NNK+BuChEcomplex based on intermolecular energies (∆G) were found to −8.57 kcal/mol, −8.21 kcal/mol, and −8.08 kcal/mol, respectively. MDS deviation and fluctuation plots of the NNAL and NNK interaction with AChE and BuChE have shown significant results. Further, Molecular Mechanics Poisson-Boltzmann Surface Area (MM‐PBSA) results shown the best total binding energy (Binding∆G) −87.381 (+/−13.119) kJ/mol during NNK interaction with AChE. Our study suggests that CSC is well capable of altering the normal biomolecular mechanism of CNS; thus, obtained data could be useful to design extensive wet laboratory experimentation to know the effects of CSC on human CNS.

Temephos is an organophosphorus pesticide used in control campaigns against vectors that transmit diseases, including dengue, a public health concern. The WHO classifies temephos in category III and its safe concentration (low-observable-adverse-effect level) in male rats is 100 mg/kg/day for up to 44 days. Temephos inhibits acetylcholinesterase (AChE) and is metabolized in different tissues, probably by mixed-function oxidases; one of its metabolites is bisphenol S (BPS), which is considered an endocrine disruptor. The aim of this study was to evaluate the effects of temephos on sperm function and its biotransformation in the testis, epididymis, and other tissues to explore its toxicity in rats treated with 100 mg/kg/day/5 or 7 days (gavage). AChE activity was inhibited 70% starting on day 3 and 13 or 41% mortality was observed at 5 or 7 days, respectively. After 7 days, temephos significantly decreased sperm motility (30%) and viability (10%) and increased (10%) lipoperoxidation, and the sperm DNA exhibited no damage. Temephos was distributed and metabolized in all tissues, with the highest levels observed in the adipose tissue and temephos levels were 16-fold higher in the epididymis than in the testis. Notably, BPS was observed in the testis. At 5 days, decreased sperm motility (12.5%) and viability (5.7%) were observed and sperm fertilization decreased (30%). These results suggest that temephos decreases sperm quality and fertilization capacity at recommended safe concentrations and that it is metabolized in male reproductive tissues. This pesticide places the reproductive health of exposed people at risk, suggesting the need to reevaluate its toxicity.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease categorized by the deficiency in the cognition and memory. Approximately 50 million peoples has the AD, which is categorized by the deficiency in the cognition, memory and other kinds of cognitive dissention. The present exploration was designed to unveil the ameliorative properties of ononin against the aluminium chloride (AlCl3)-provoked AD in animals via the suppression of oxidative stress and neuroinflammation. AD was provoked to the Sprague Dawley rats through administering orally with 0.5 ml/100 g b.wt. of AlCl3 25 days and then supplemented with the 30 mg/kg of ononin orally for 25th day to 36th day. The behavioural changes were examined using open field and Morris Water Maze test. The acetylcholine esterase (AChE) activity was studied by standard method. The status of Aβ1-42, MDA, SOD, total antioxidant capacity (TAC) were quantified using respective assay kits. The interleukin(IL)-1β and TNF-α, BDNF, PPAR-γ, p38MAPK, and NF-κB/p65 status was quantified using respective assay kits. Brain histology was studied using microscope. The ononin treatment effectively modulated the AlCl3-triggered behavioural alterations in the AD animals. Ononin appreciably suppressed the AChE, Aβ1-42, and MDA and improved the SOD and TAC in the brain tissues of AD animals. The status of IL-1β, TNF-α, p38MAPK, and NF-κB were suppressed and the BDNF and PPAR-γ contents were elevated in the brain tissues of AD animals. The outcomes brain histology analysis proved the attenuate role of ononin. Our findings recommended that the ononin treatment could ameliorate the cognitive impairment, suppress the neuroinflammation and oxidative stress in the AD animals.

Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.

Triclosan (TCS) used commonly in pharmaceuticals and personal care products has become the most common pollutant in water. Three days old hatchlings of an indegenous fish, Labeo rohita were given 96h exposure to an environmentally relevant (0.06mg/L) and two moderately lethal concentrations (0.067 and 0.097 mg/L) of TCS and kept for 10 days of recovery for recording transcriptomic alterations in antioxidant/detoxification (SOD, GST, CAT, GPx, GR, CYP1a and CYP3a), metabolic (LDH, ALT and AST) and neurological (AchE) genes and DNA damage. The data were subjected to Principal Component Analysis (PCA) for obtaining biomarkers for the toxicity of TCS. Hatchlings were highly sensitive to TCS (96h LC 50 = 0.126mg/L and risk quotient = 40.95), 96h exposure caused significant induction of CYP3a, AChE and ALT but suppression of all other genes. However, expression of all the genes increased significantly (except for a significant decline in ALT) after recovery. Concentration dependent increase was also observed in DNA damage [Tail Length (TL), Tail Moment (TM), Olive Tail Moment (OTM) and Percent Tail DNA (TDNA)] after 96h. The damage declined significantly over 96h values at 0.06 and 0.067 mg/L after recovery, but was still several times more than control. TCS elicited genomic alterations resulted in 5-11% mortality of exposed hatchlings during the recovery period. It is evident that hatchlings of L. rohita are a potential model and PCA shows that OTM, TL, TM, TDNA, SOD and GR (association with PC1 during exposure and recovery) are the biomarkers for the toxicity of TCS.

Senecio angulatus L.f. is a flowering plant from the Asteraceae family that is native to South Africa and which was observed recently in the north and the east of Algeria. This study was aimed for the first time, to evaluate concomitantly phytochemical profiles, using LC-ESI/MS analysis, following by testing and assessing in vitro antioxidant and antiacetylcholinesterase activities of these specific species. The results indicated that the hydromethanolic and the acetate extracts have shown remarkable potent inhibitory effects on AChE with IC50 of (6.04 ± 0.05; 6.72 ± 0.10 µg/mL) respectively along with antioxidant potential of acetate for FRAP and phenanthroline methods with A0.5 of (11.15 ± 0.72; 5.72 ± 0.13 µg/mL) successively. Moreover, a high amount of cynarin and trans-ferulic acid was found in this extract whilst butanolic extract has recorded the highest amount of chlorogenic acid. Indeed phenolic compounds usually have a hydroxyl in their structure which may contribute significantly to the antioxidant activity.

—Acute cerebral ischemia initiates a pathway that can result in the development of oxidative stress and disruption of the balanced functioning of some neurotransmitter systems in the brain. The protective effects of therapeutic hypothermia in ischemia are well known and studied, however, the mechanisms of its effect on the cholinergic system of the brain, closely related to the functioning of acetylcholinesterase (AChE), remain unclear. In this work, we investigated the activity and kinetic parameters of AChE, as well as the relationship between its catalytic properties and the intensity of free radical processes in the synaptic terminals of neurons in the rat brain in occlusion of the carotid arteries under normothermia and moderate (33°C) hypothermia. It was found that cerebral ischemia leads to a decrease in AChE activity, whereas hypothermia during carotid artery occlusion prevents this decrease. In cerebral ischemia, the Vmax value and the efficiency of AChE catalysis decreases, whereas Ki increases, which along with unchanged Km values, contributes to an increase in the range of effective acetylthiocholine concentrations and [S]opt values. Mild hypothermia during cerebral ischemia prevents significant changes in the kinetic parameters of the enzyme. Ischemia stimulates the processes of oxidative destruction of membrane proteins and lipids. Hypothermia during ischemia prevents an increase in the level of lipid and protein oxidative modification products, as well as superoxide dismutase activity in synaptosomes. A negative correlation was found between the kinetic parameters of AChE and the levels of products of oxidative modification of lipids and proteins of synaptosomes. This indicates an important role of reactive oxygen species in modulating the activity of a key enzyme of the cholinergic system. The results obtained allow us to conclude that hypothermia during ischemia prevents the activation of free radical processes in the synaptic terminals of neurons, which, in turn, prevents a decrease in the activity and efficiency of AChE catalysis.

The subterranean termite Reticulitermes chinensis Snyder is an important pest in China. We determined the inhibition of six selected insecticides to acetylcholinesterase (AChE) extracted from R. chinensis. Our results yielded half maximal inhibitory concentrations (I50) for each of the insecticides to be 3.49 × 10–3 M for methomyl, 3.87 × 10–2 M for phoxim, 2.18 × 10–3 M for triazophos, 1.89 × 10–3 M for profenosos, 1.10 × 10–3 M for malathion, and 4.39 × 10–2 M for omethoate. Furthermore, the inhibitory activity of AChE by the six insecticides was increased with the increase of insecticide concentration from 3.3 × 10–7 to 5 × 10–3 M. These results provide a theoretical basis for the management of R. chinensis.

Concurrent exposure to a multitude of environmental toxicants pose serious health hazard to humans and animals. The present investigation was conceptualized to determine deleterious effects of concomitant subacute arsenic and quinalphos exposure on antioxidant responses of liver and erythrocytes of Wistar rats. Fifty-four Wistar rats were divided into nine groups with six animals in each. Animals were exposed to either quinalphos (1/100th and 1/10th of LD50) through oral gavage daily or arsenic (50 and 100 ppb) in drinking water alone and in combination for 28 days. While treatment with different toxicants alone also significantly reduced hemoglobin concentration, hepatic biomarkers and levels of antioxidant parameters as compared with control values, concomitant exposure significantly (P

Hippeastrum elegans is a Brazilian Amaryllidaceae plant producing galantamine (GAL), an anticholinesterase drug for Alzheimer's disease, besides other alkaloids such as pseudolycorine (PSE), narciclasine (NAR) and sanguinine (SAN). Therefore, we used a metabolomic approach to investigate the influence of the harvest time on its chemical composition and acetylcholinesterase activity (AChE). Alkaloid extracts were analyzed by UPLC-ESI-MS and 1H NMR, then assessed for AChE inhibitory activity. These data were combined and analyzed by Partial Least Square (PLS) regression. H. elegans was found to be rich in PSE and NAR, achieving higher contents in 270 and 390 days of cultivation, respectively. However, the highest anti-AChE activities were observed for 450 days-bulbs extracts. PLS indicated pseudolycorine as the discriminant compound for this extract, hence responsible for its higher anti-AChE activity jointly with the known AChE inhibitors GAL and SAN. Thus, the cultivation of H. elegans appears to be a promising way for providing bioactive alkaloids.

The aim of this study was to investigate the antibacterial and acetylcholinesterase (AChE) inhibitory activities of 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl)benzenesulfonamides (compounds 1 – 12) and to find out new possible drug candidate molecules since the available agents in clinical use have some limitations. According to the results of antibacterial screening for compounds 1 – 12, most of the synthesized compounds were found to be effective against Gram-positive microorganisms while being ineffective (MIC > 1600 μg/mL) on Gram-negative microorganisms. According to the AChE inhibition results, Ki values of compounds 1 – 12 were in the range of 5 ± 1 – 34 ± 2 nMtoward AChE. Tacrine (TAC) used as a reference drug had Ki value of 4 ± 1 nM toward AChE. The non-substituted derivative compound 1 coluld be considered as a lead compound for this study in terms of AChE inhibitory activity, since its Ki value (5 ± 1 nM) was close to that of the reference drug (TAC). Thus, compound 1 was docked at the binding site of AChE and showed good interaction with the target enzyme, suggesting their possible mechanism of action.

Donepezil is a centrally acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central versus peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg sc), neostigmine methyl sulfate (80 or 240 μg/kg ip), atropine sulfate (5 mg/kg ip), atropine methyl bromide (5 mg/kg ip), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36 ± 4% and 44 ± 3% compared with saline ( n = 10, P < 0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13 ± 2% and 22 ± 2% compared with saline ( n = 6, P < 0.001). Modest ( P < 0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice coadministered atropine sulfate; however, coadministration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature, but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high-frequency HR variability. We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via the activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice. Moreover, the combination of compound 6 and morphine has a synergistic effect. We intended to explain the molecular mechanism of this effect. Therefore, 36 analgesic-related targets (including 15 G protein-coupled receptors, 6 enzymes, 13 ion channels, and 2 others) were systemically evaluated using reverse docking. The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase (AChE) or α4β2 nicotinic acetylcholine receptor (nAChR). This study provides practitioners a new insight of analgesic effects.

Culex pipiens (L.) (Diptera: Culicidae) is the most important medical insect in many parts of the world. Biological and natural chemicals have many advantages over the traditional ones in case of mosquito control. The efficacy of two insecticides belonging to different groups chlorpyrifos-ethyle (oranophosphate) and Bacillus thuranginsis var israelinsis) (bio-insecticides)were evaluated against the field and laboratory individuals of late 3rd instar larvae of Culex pipiens at different concentrations and three periods of exposure under laboratory conditions. Results obtained showed that the laboratory strain showed higher susceptibility to the tested insecticides than the mosquito populations collected from Abo-Rewash City, Giza Governorate and the mortality percentage was increased gradually with increasing the insecticide concentrations and the mortality percentage showed significant differences between concentrations and control. Also, The activity of acetyl cholinesterase (AChE), the glutathione S- transferase (GST), Total proteins and the activities of both Aspartate aminotransferase AST(GOT) and Alanine aminotransferase ALT(GPT) were determined were determined after 72 hrs of insecticidal exposure.

Graphical abstract, Highlights • Diazinon perturbs CNS function via multiple mechanisms. • Oxidative stress is one of the main causes of diazinon-induced neurodegeneration. • Gene expression may be affected by diazinon exposure. • Diazinon administration may increase anxiety and depressive-like behaviors. • Spatial learning and short and long-memory are severely affected by diazinon., Diazinon (DZN) with prominent neurotoxic effects perturbs CNS function via multiple mechanisms. This investigation intends to explore mood, spatial learning, and memory dysfunction, acetylcholine esterase (AChE) activity, and neurodegeneration-related gene expression in the cortex and hippocampus regions of mice exposed to DZN for 63 consecutive days (subchronic exposure). Adult male albino mice were orally given sublethal DZN (DZNL = 0.1 mg/kg, DZNM = 1 mg/kg and DZNH = 10 mg/kg). All mice in the DZNH group died within 3 weeks postexposure. DZNL and DZNM caused body and brain weight loss (p

Alzheimer’s is a progressive mental deterioration associated with the degeneration of the cognition activities and memory loss. It is considered to be a multifactorial disease. One of the causes of the Alzheimer’s disease is the low concentration of the neurotransmitter named acetylcholine (ACh) at the synaptic cleft. Thus, inhibitor of Acetylcholinesterase (AChE), an enzyme whose function is to degrade the acetylcholine, is proved to be a promising candidate to treat this disease. Among the inhibitors are the natural alkaloids that also have an inhibitory effect on the AChE. In this study we have focused on the simple derivates of beta carbolime (a group of alkaloids) and studied their interaction with AChE via rigid protein-ligand docking approach.

Although radical treatment of Alzheimer’s and Parkinson’s disease is not possible yet, it is aimed to slow the course of the disease and increase the life quality of individuals with the drugs used in the clinic at the present time. Successful results have been achieved in the use of cholinesterase inhibitors and monoamine oxidase inhibitors together in these neurodegenerative diseases. In this study, indane ring which are in the structure of anticholinesterase effective molecules and 2-hydrazinothiazole structure whose inhibitory activities reported on monoamine oxidase-B (MAO-B) were combined; 4-(substituted phenyl)-2-[2-(3-phenyl-2,3-dihydro-1H-inden-1-ylidene) hydrazinyl]thiazole derivatives (3a–3i) were synthesized as dual inhibitors. The structures of the compounds were verified by IR, 1H-NMR, 13C-NMR, and HRMS spectroscopy. When enzyme inhibition activities were evaluated, it was determined that the compounds 3a (42.33%) and 3d (42.39%) on acetylcholinesterase (AChE) enzyme; compounds 3g (75.42%) and 3h (60.33%) showed inhibition on MAO-B enzyme at most, at 10−3 M concentration.

This research study is mainly focused to evaluate the anti-parasitic, insecticidal, cytotoxic and anti-alzheimer potential of various leaf extracts of Ajuga bracteosa Wallich ex Bentham. 04 different extracts were prepared using solvent of different polarity to determine the best candidate for potent bioactivity i.e. n-hexane (NH), Ethyl acetate (EA), Ethanol (EL) and Chloroform (CH). Concentrations of each extracts were made specified for all activities. All extracts were exploited for broad range of biomedical applications including leishmaniasis, in vitro anti-Alzheimer, insecticidal and cytotoxic studies. Our results showed that A. bracteosa n-hexane extract was highly active against Leishmania Tropica with significant inhibition of 58 ± 1.61 for promastigote and 63 ± 2.29 for amastigote at 1000 μg/mL. Furthermore, promising anti-alzheimer activity acetylcholinesterase (AChE) 46 ± 0.83 and butrylcholineterase (BChE) 49 ± 1.17 was noted for n-hexane. The insecticidal potential of these extracts were test against five different insects (Rhyzopertha dominica, Trogoderma granarium, Tribolium castaneum, Sitophilus oryze, and Callosobruchus analis). The higest mortality rate of insecticidal activity was recorded by n-hexane followed by Ethyl acetate whereas ethanol extract was found to be less effective against all the test species. Significant cytotoxic potential of each plant sample against Artemia salina thus aware us for further detailed research to find out novel drugs. Based on our results we believe that Ajuga bracteosa could be used to develop as a potential botanical insecticide against different insect and pests, such as aphids as well as an excellent source for the compound isolation as anti-tumor agent.

The study was conducted to explore the anticholinesterase inhibition property of eugenol derived molecules. Ten eugenol derivatives were synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by Ellman’s method. Most of the tested derivatives showed higher inhibition on BChE than AChE, however, their overall inhibitory activity was weak. In contrast, three derivatives (compounds 3,6,9) showed higher and good AChE inhibitory activity of more than 50% inhibition at 10 μg/mL. Among them, compound 9bearing a ethyl substituent at para position of the benzoyl ring showed the most potent AChE inhibition, with IC50 of 5.64 μg/mL. Ligand-protein docking simulation was also performed for the most active derived molecules (compounds 3,6,9).

The comparative toxic effect of Vertimec®1.8% EC, Fast Max Super®8.4% SC and nano-derived form of abamectin (ABM) (1% nano-emulsion) as a dermal contact for 48 h against land snail,Helix aspersawas evaluated at laboratorial trail. Acute toxicity values (LD50) were 6.45, 11.97, and 45.95 µg snail-1for nano-derived form of ABM, Fast Max Super®and Vertimec®, respectively. Nano-derived form exhibited the highest toxic effects (1.86 and 7.12-folds), respect to Fast Max Super®and Vertimec®. Sublethal doses: 1/10 and 1/100 LD50sof the examined compounds were applied to evaluate some biochemical alterations e.g. acetylcholinesterase (AChE), malondialdhyde (MDA), lactate dehydrogenase (LDH), glutathione-S-transferase (GST), acid phosphatase (ACP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), respectively, in haemolymph and digestive glands homogenates. The all treatments significantly decreased AChE activity in ganglia homogenate, respect to control group (untreated). All treatments exhibited MDA level and LDH activity greater than the control in both haemolymph and digestive gland. This concept recognizes the cytotoxic effect of ABM on gastropods. Significant declines in GST, ACP, and ALP activities were exhibited in homogenate of digestive gland for the all treatments. However, AST/ALT activities exhibited increase greater than untreated group. These findings may explain the role of these doses of ABM for dysfunction in organs ofH. aspersa. Thus, prepared nano-emulsion was more potent toxic on land snails. However,H. aspersais considered a useful tool to assess ecotoxicological impact of pesticides.

A series of 2-(3-hydroxybenzyl)benzo[d]isothiazol-3(2H)-one Mannich base derivatives were designed as potential multifunctional agents against Alzheimer’s disease. The twelve derivatives were synthesized and evaluated with various biological activities. In vitro, biological assays showed that most of the target compounds are selective AChE inhibitors and good antioxidants. Among them, compounds 6d and 13d are representative agents exhibiting significant selective AChE inhibition (IC50 = 1.09 µM and 2.01 µM, respectively), potent antioxidant activity, moderate inhibition of self-induced Aβ1–42 aggregation, selective metal-chelating activity with Fe2+ and Cu2+, excellent neuroprotective effect on H2O2-induced PC12 cell injury and good BBB permeability. Moreover, the step-down passive avoidance test demonstrated that 6d and 13d can improve the scopolamine-induced cognitive deficit in mice. The above results suggested that compounds 6d and 13d can be envisioned as multifunctional lead compounds for further development of drugs against AD.

This study evaluated the ameliorative impact of Nigella sativa oil (NSO) on emamectin benzoate (EMB) neurotoxicity. Thirty-five male rats were randomly allocated into 5 groups (n = 7). G1 (control): received distilled water; G2: received NSO (3 ml. Kg-1 B.W.) for 6 weeks; G3: received EMB (9 mg kg-1 B.W.) for 6 weeks; G4: was co-treated with NSO and EMB for 6 weeks; G5: was treated with EMB for 4 weeks then, received NSO for 2 weeks. All treatments were given orally every other day. EMB increased serum urea, creatinine levels; brain dopamine, serotonin, malondialdehyde levels; brain expression levels of caspase 3 and TNF-α. While, it decreased serum total protein, albumin, brain GABA, AChE, GSH-Px, CAT, and SOD levels. Histopathological findings revealed hemorrhage, congestion, severe degeneration, and edema of the brain tissues. NSO reversed the EMB-induced biochemical and histopathological alterations. This NSO effect is mostly due to its antioxidant, antiinflammatory, and antiapoptotic activities. These findings suggest NSO as a potential protective and therapeutic agent for EMB-induced neurotoxicity.

A series of 1-[aryl-(thiazol-2-ylamino)-methyl]-naphthalen-2-ol derivatives were synthesized using porcine pancreatic lipase as a catalyst. The major assets of this methodology were use of biocatalyst, non-toxic organic medium, mild reaction condition and good-to-excellent yield of desired products. The synthesized Betti bases were evaluated for in vitro anti-cholinesterase activity. Test compounds exhibited potential inhibitory activities towards AChE (IC50 = 0.82 to 4.27 µM) as well as BuChE (IC50 = 2.18 to 9.64 µM). Compound 4g exhibited highest inhibitory activity for both AChE (IC50 = 0.82 ± 0.05 µM) and BuChE (IC50 = 2.18 ± 0.21 µM) when compared to standard reference drug galantamine inferring that it acts a dual AChE/BuChE inhibitor. Kinetic studies of compound 4g suggested a mixed-type inhibition towards both AChE and BuChE with Ki values of 8.82 μM and 12.41 μM, respectively. Further, cell viability assay that compound 4(a–j) do not impart any toxicity to N2a cells. In addition, molecular docking studies were performed to corroborate the biological results. This is the first report on lipase-catalysed synthesis of Betti bases as well as for their potential in vitro anti‐Alzheimer activity.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are considered as viable targets in the treatment of Alzheimer’s disease and other dementias. However, since clinically used AChE or du...

Introduction: Neuroactive herbal drugs enriched with antioxidants are valuable in treating neurocognitive dysfunction and Vaccinium corymbosum, enriched with antioxidant phytochemicals, is used for treating memory disorders. Hence, the present study evaluated the neuroprotective effects of ethanolic extract of Vaccinium corymbosum (EEVC) on aluminium chloride(AlCl3)-induced Alzheimer’s type of dementia and haloperidol-induced catalepsy-associated behavioural changes. Methods:In vitro antioxidant potential was evaluated using 1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS). The total phenolic content (TPC) was quantified. For in vivo studies, AlCl3 (100 mg/kg) was orally administered for 42 days, whereas the EEVC was administered on the 21st day until the 42nd day in two doses (200 mg/kg and 400 mg/kg). In the haloperidol-induced group, EEVC was treated for 21 days, and haloperidol (1 mg/kg) was administered to induce behavioural changes. Open-field, Y-Maze and traction tests were performed, and the mice brain acetylcholinesterase (AChE) enzyme was determined. Results: IC50 values in DPPH and ABTS assays were 85.5 μg/mL and 80 μg/mL, respectively and the total phenolic content of EEVC was found to be 0.166 mg. In a behavioral study, animals treated with 200 mg/kg and 400 mg/kg of EEVC exhibited a neuroprotective impact on AlCl3-induced neurodegeneration and haloperidol-induced behavioral changes with significant inhibition (P < 0.05 and P < 0.01, respectively) in acetylcholinesterase enzyme. Conclusion: The neuroprotection by EEVC postulated that it is a promising therapeutic agent for treating behavioral and cognitive dysfunctions. Further investigations on pro-inflammatory cytokine and neuroendocrine regulation in transgenic Alzheimer’s disease (AD)models complement the therapeutic value of V. corymbosum.

Objectives This study investigates protection against oxidative stress and memory enhancing potential of long-term consumption of Moringa oleifera leaves. Methods Male Wistar rat were fed with mixture of M. oleifera-supplemented diets (MOSD) partitioned in 1, 5, 10, and 20% continuously for 12 weeks. Object recognition test (ORT) and Morris water maze (MWM) was used for assessing neurocognition. Changes in body weight, Lipid peroxidation (MDA), Glutathione (GSH), Catalase (CAT) and Acetylcholinesterase (AChE) activity was assayed in the brain tissue. Histomorphometric of the hippocampus was also examined. Results The diets progressively increase the body weigh after the 12 weeks, improved spatial (MWM) and non-spatial (ORT) memory performance, protect against oxidative stress, inhibit AChE activity and suppresses neuronal degeneration in the hippocampus when stained with Cresyl violent stain. Conclusions Conclusively, long-term consumption of MOSD shows strong protection against oxidative stress and hippocampal degeneration and improves neurocognition with dose dependent effect.

Cucurbita pepo is used as a vegetable in Pakistan and its seeds are also rich in tocopherol. Data showed the pivotal role of tocopherol in the treatment of Parkinson's disease (PD). The current study was designed to probe into the antiparkinson activity of methanolic extract of C. pepo (MECP) seeds in the haloperidol-induced Parkinson rat model. Behavioral studies showed improvement in motor functions. The increase in catalase, superoxide dismutase, glutathione levels whereas the decreases in the malondialdehyde and nitrite levels were noted in a dose-dependent manner. Acetylcholine-esterase (AchE) activity was increased. Molecular docking results revealed significant binding interaction of selected phytoconstituents within an active site of target protein AchE (PDB ID: 4EY7). Furthermore, α-synuclein was up regulated with down regulation of TNF-α and IL-1β in the qRT-PCR study. Subsequently, ADMET results on the basis of structure to activity predictions in terms of pharmacokinetics and toxicity estimations show that selected phytochemicals exhibited moderately acceptable properties. These properties add knowledge towards the structural features which could improve the bioavailability of selected phytochemicals before moving towards the initial phase of the drug development. Our integrated drug discovery scheme concluded that C. pepo seeds could ameliorate symptoms of PD and may prove a lead remedy for the treatment of PD.

BACKGROUND Terrestrial snails are one of the most damaging threats to sustainable agriculture. Chemical control using molluscicides is the main approach used to combat these agricultural pests. Metaldehyde is the active ingredient in most snail control products in use. However, its toxicity indices and mode of action have scarcely been investigated. For the first time, we characterized the metaldehyde contact toxicity indices against the white garden snail Theba pisana. The biochemical impact of metaldehyde on acetylcholinesterase (AChE), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), alkaline phosphatase (ALP) and glutathione S-transferase (GST) activities and the lipid peroxidation (LPO) level was investigated. RESULTS The median lethal dose (LD50 ) values at 24, 48 and 72 h of treatment were 11.33, 8.53, and 6.87 μg g-1 body weight (BW), respectively; while, the median lethal time (LT50 ) values were 88.16, 55.85, and 25.67 h when doses of 6, 8, and 12 μg g-1 BW were applied, respectively. In the snails treated with 2.83 and 5.67 μg g-1 BW (¼ and ½ LD50 at 24 h of treatment) and 2.13 and 4.27 μg g-1 BW (¼ and ½ LD50 at 48 h of treatment), higher AChE, GST, AST, ALT, and ALP activities as well as higher levels of LPO were observed compared with that of untreated snails. CONCLUSION Metaldehyde displayed dose- and time-dependent contact toxicity. The biochemical results suggest that metaldehyde may have neurotoxic and cytotoxic actions in terrestrial snails. Application of metaldehyde in ways that could control pest snails and slugs and reduce its negative impact on the environment are discussed. © 2021 Society of Chemical Industry.

Inhibition kinetics assays were conducted with 16 commercial organophosphate (OP) pesticides or their metabolites on acetylcholinesterase (AChE) in erythrocyte “ghost” preparations from 18 individual humans (both sexes; adults, juveniles, and cord blood samples; mixed races/ethnicities) and pooled samples from adult rats (both sexes). A well-established spectrophotometric assay using acetylthiocholine as substrate and a chromogen was employed. The kinetic parameters bimolecular rate constant (ki), dissociation constant (KI), and phosphorylation constant (kp) were calculated for each compound. As expected, a wide range of potencies were displayed among the tested compounds. Statistical analysis of the resultant data indicated no differences in sex, age, or race/ethnicity among the human samples that are unexpected based on chance (4.2% statistically significant out of 48 parameters calculated) and no differences between the sexes in rats. The bimolecular rate constants for 10 of the compounds were not statistically different between rats and humans. The data indicate that, consistent with the high level of conservation of AChE among species and the fact that AChE at different locations within a species arises from the same gene, the inhibition kinetic parameters calculated from rat erythrocyte ghost preparations should be useful in estimating potencies of OP compounds on target AChE in humans. Additionally, the data indicate that differences in sensitivities among individual humans were not apparent.

Background: There are millions of workers in the world, who engage in activities associated with welding operations but are not classified as full-time metal workers. The present study aimed to determine the activity of acetylcholinesterase (AChE) in blood of laboratory animals exposed to welding fumes. Methods: Welding fumes were obtained from Kofar Ruwa, Kano by a skilled welder. 130 albino rats were purchased from the Animal Section of Department of Biological Sciences and were divided into 12 groups. They were given doses equivalent to the workers’ real life exposure regimes, and 1 group was selected as control group. They were administered intratracheally following anesthetization once weekly for twelve weeks. The rats were euthanized and serum samples were collected. Then, AChE activity was evaluated spectrophotometrically using ELISA kit (Sunlong Biotech Company). Results: The mean values of AChE ranged from 23.1 to 25.05 ng/mL with the control having a value of 24.7 ng/mL. Thus, there was a decrease in the values of AChE in the blood of treated groups, which was significantly different from the control (P