Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer\'s disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.

BACKGROUND: Adolescents living in agricultural communities may be at risk for the adverse effects of pesticide exposure because they are involved in agriculture either as a career or to support their families.
OBJECTIVE: The purpose of this study was to investigate the association of farm activities related to pesticide exposure on blood cholinesterase (ChE) levels among adolescents from farming families in the north of Thailand.
METHODS: This cross-sectional study included 336 adolescents aged 12-19 years from farming families in Chiang Dao District, Chiang Mai Province. Data on pesticide exposure was collected using a questionnaire, and blood ChE activity was assessed using a ChE reactive paper test kit via fingerstick blood sampling.
RESULTS: Overall, 51.2% of participants had abnormal blood ChE levels. Univariable logistic regression analysis revealed that pesticide-related activities on farms associated with abnormal ChE levels were mixing/spraying (OR=10.54; 95%CI=4.63-23.99), assisting or working in areas with pesticide application (OR=5.54; 95%CI=3.45-8.89), and harvesting (OR=3.70; 95%CI=2.35-5.82). In a multivariable model (Nagelkerke R2=0.374), mixing/spraying (OR=4.90; 95%CI=2.03-11.83) and assisting or working in areas with pesticide application (OR=2.61; 95%CI=1.49-4.57) were significantly associated with abnormal ChE levels, but harvesting (OR=1.48; 95%CI=0.84-2.61) was not significant after adjusting for sex, age in years, and entering or walking through a farm.
CONCLUSIONS: The findings indicated that Thai adolescents living in farming families are at risk of pesticide exposure, particularly those involved in agricultural activities such as pesticide applicators. An intervention and measure to raise awareness and reduce the risk of pesticide exposure in adolescents is required.

The main feature of neurodegenerative diseases, including Alzheimer\'s disease, is the network of complex and not fully recognized neuronal pathways and targets involved in their onset and progression. The therapeutic treatment, at present mainly symptomatic, could benefit from a polypharmacological approach based on the development of a single molecular entity designed to simultaneously modulate different validated biological targets. This strategy is principally based on molecular hybridization, obtained by linking or merging different chemical moieties acting with synergistic and/or complementary mechanisms. The coumarin core, widely found in nature, endowed with a recognized broad spectrum of pharmacological activities, large synthetic accessibility and favourable pharmacokinetic properties, appears as a valuable, privileged scaffold to be properly modified in order to obtain compounds able to engage different selected targets. The scientific literature has long been interested in the multifaceted profiles of coumarin derivatives, and in this review, a survey of the most important results of the last four years, on both natural and synthetic coumarin-based compounds, regarding the development of anti-Alzheimer\'s compounds is reported.

The widespread use of organophosphate (OP) and carbamate (CM) pesticides requires efficient and cost-effective detection methods. This study introduces a micro-electrometric method using cricket cholinesterase (ChE) to detect OP and CM residues, providing a rapid and economical alternative to conventional chromatographic techniques. The parameters of the method, including the substrate concentration, incubation temperature, and incubation time, were optimized. By leveraging the sensitivity of cricket ChE to OP and CM inhibition, this approach translates enzyme inhibition into an electrical signal to quantify pesticide levels, achieving an impressive limit of detection (LOD) from 0.036 to 0.086 parts per million (ppm). This method demonstrated reproducibility and stability, making it suitable for field applications and on-site testing across various environmental matrices. This research represents a significant advancement in pesticide residue analysis with potential applications in the development of portable biosensor devices for real-time environmental monitoring and public health protection.

BACKGROUND: The study investigated the effect of co-administration of curcumin and donepezil on several markers of cognitive function (such as spatial memory, astrocyte activation, cholinesterase expressions) in the brain cortex and hippocampus of scopolamine-treated rats.
RESULTS: For seven consecutive days, a pre-treatment of curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) was administered. On the seventh day, scopolamine (1 mg/kg) was administered to elicit cognitive impairment, 30 min before memory test was conducted. This was followed by evaluating changes in spatial memory, cholinesterase, and adenosine deaminase (ADA) activities, as well as nitric oxide (NO) level were determined. Additionally, RT-qPCR for glial fibrillary acidic protein (GFAP) and cholinesterase gene expressions was performed in the brain cortex and hippocampus. Also, GFAP immunohistochemistry  of the brain tissues for neuronal injury were performed in the brain cortex and hippocampus. In comparison to the control group, rats given scopolamine had impaired memory, higher levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ADA activities, as well as elevated markers of oxidative stress. In addition to enhanced GFAP immunoreactivity, there was also overexpression of the GFAP and BChE genes in the brain tissues. The combination of curcumin and donepezil was, however, observed to better ameliorate these impairments in comparison to the donepezil-administered rat group.
CONCLUSIONS: Hence, this evidence provides more mechanisms to support the hypothesis that the concurrent administration of curcumin and donepezil mitigates markers of cognitive dysfunction in scopolamine-treated rat model.

Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer\'s disease by targeting neuroinflammation and cholinesterases. Molecular docking revealed that colchicine\'s hydrophobic trimethoxyphenyl framework can potentially bind to the peripheral anionic site of cholinesterases. Hybrid structures combining colchicine with aryl/alkyl amines were designed to bind both peripheral and catalytic sites of cholinesterases. We describe here the design, synthesis, and in vitro cytotoxicity evaluation of these colchicine-aryl/alkyl amine hybrids, along with their in silico interactions with the cholinesterase active site gorge. Nontoxic analogs demonstrating strong cholinesterase binding affinity were further evaluated for their anticholinesterase and antineuroinflammatory activities. The colchicine-donepezil hybrid, SBN-284 (3x), inhibited both acetylcholinesterase and butyrylcholinesterase as well as the NLRP3 inflammasome complex at low micromolar concentrations. It achieved this through noncompetitive inhibition, occupying the active site gorge and interacting with both peripheral and catalytic anionic sites of cholinesterases. Analog 3x was shown to cross the blood-brain barrier and exhibited no toxicity to neuronal cells, primary macrophages, or epithelial fR2 cells. These findings highlight the potential of this lead compound for further preclinical investigation as a promising anti-Alzheimer agent.

Cholinesterases are well-known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer\'s, and lipid metabolism. The protonation pattern of active sites of cholinesterases influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Despite its significance, our comprehension of the fine structure of cholinesterases remains limited. In this study, we employed enhanced-sampling quantum-mechanical/molecular-mechanical calculations to show that cholinesterases predominantly operate as dynamic mixtures of two protonation states. The proton transfer between two non-catalytic glutamate residues follows the Grotthuss mechanism facilitated by a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations and calls for special treatment. The calculated proton transfer barrier of 1.65 kcal/mol initiates a discussion on the potential existence of two coupled low-barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase-related protein and drug design studies.

Alzheimer\'s disease (AD) is a progressive multifaceted neurodegenerative disease and remains a formidable global health challenge. The current medication for AD gives symptomatic relief and, thus, urges us to look for alternative disease-modifying therapies based on a multitarget directed approach. Looking at the remarkable progress made in peptide drug development in the last decade and the benefits associated with peptides, they offer valuable chemotypes [multitarget directed ligands (MTDLs)] as AD therapeutics. This review recapitulates the current developments made in harnessing peptides as MTDLs in combating AD by targeting multiple key pathways involved in the disease\'s progression. The peptides hold immense potential and represent a convincing avenue in the pursuit of novel AD therapeutics. While hurdles remain, ongoing research offers hope that peptides may eventually provide a multifaceted approach to combat AD.

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Chlorpyrifos is an organophosphate pesticide associated with numerous health effects including motor performance decrements. While many studies have focused on the health effects following acute chlorpyrifos poisonings, almost no studies have examined the effects on motoneurons following occupational-like exposures. The main objective of this study was to examine the broad effects of repeated occupational-like chlorpyrifos exposures on spinal motoneuron soma size relative to motor activity. To execute our objective, adult rats were exposed to chlorpyrifos via oral gavage once a day, five days a week for two weeks. Chlorpyrifos exposure effects were assessed either three days or two months following the last exposure. Three days following the last repeated chlorpyrifos exposure, there were transient effects in open-field motor activity and plasma cholinesterase activity levels. Two months following the chlorpyrifos exposures, there were delayed effects in sensorimotor gating, pro-inflammatory cytokines and spinal lumbar motoneuron soma morphology. Overall, these results offer support that subacute repeated occupational-like chlorpyrifos exposures have both short-term and longer-term effects in motor activity, inflammation, and central nervous system mechanisms.