Derivatives of Amodiaquine as Potent Human Cholinesterases Inhibitors: Implication for Treatment of Alzheimer's Disease.

As some previously reported studies have proven that amodiaquine, in addition to its primary antimalarial activity, also has potential for new applications such as the inhibition of cholinesterases, in our study we focused on the evaluation of the influence of different substituents in the aminoquinoline part of the amodiaquine structure on the inhibition of human acetylcholinesterase and butyrylcholinesterase to investigate the possibility for their use as drugs for the treatment of AD. We synthesized a series of amodiaquine derivatives bearing H-, F-, CF-, NO-, CN-, COH- or CHO- groups on the aminoquinoline ring, and determined that all of the tested derivatives were very potent inhibitors of both cholinesterases, with inhibition constants () in the nM and low μM range and with prominent selectivity (up to 300 times) for the inhibition of acetylcholinesterase. All compounds displayed an ability to chelate biometal ions Fe, Zn and Cu and an antioxidant power comparable to that of standard antioxidants.

Apex carnivores coping with metal(loid) pollution and oxidative stress: Biological and environmental drivers of variation in kidney of European brown bear.

Induction of oxidative stress and the associated lipid peroxidation is a prevalent mechanism through which certain metal(loid)s exert nephrotoxic effects in mammals. Research on the toxic impacts of metal(loid)s in free-ranging large mammals at high trophic positions is exceedingly rare, yet crucial for understanding environmental exposure scenarios relevant to both human and animal risk assessment. Renal cortex tissues (N = 457) of free-ranging brown bears (Ursus arctos) from the Dinara-Pindos population sampled in Croatia were analysed herein for toxic metal(loid)s and the underlying biological and environmental drivers of variation, with their time trend monitored during the 2009-2022 period.

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability.

The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system's activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 -alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics.

Effects of concomitant use of THC and irinotecan on tumour growth and biochemical markers in a syngeneic mouse model of colon cancer.

Clinical treatment with the antineoplastic drug irinotecan (IRI) is often hindered by side effects that significantly reduce the quality of life of treated patients. Due to the growing public support for products with Δ-tetrahydrocannabinol (THC), even though relevant scientific literature does not provide clear evidence of their high antitumour potential, some cancer patients take unregistered preparations containing up to 80 % THC. This study was conducted on a syngeneic colorectal cancer mouse model to test the efficiency and safety of concomitant treatment with IRI and THC.

Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease.

The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity.

The effects of simvastatin and fenofibrate on malondialdehyde and reduced glutathione concentrations in the plasma, liver, and brain of normolipidaemic and hyperlipidaemic rats.

The objective of study was to investigate the effects of different doses of simvastatin and fenofibrate on malondialdehyde (MDA) and reduced glutathione (GSH) in the plasma, liver, and brain tissue of male normolipidaemic and hyperlipidaemic rats. Normolipidaemic (Wistar) rats were receiving 10 or 50 mg/kg a day of simvastatin or 30 or 50 mg/kg a day of fenofibrate. Hyperlipidaemic (Zucker) rats were receiving 50 mg/kg/day of simvastatin or 30 mg/kg/day of fenofibrate.

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

To contribute new information to the pyrethroid pesticide α-cypermethrin toxicity profile, we evaluated its effects after oral administration to Wistar rats at daily doses of 2.186, 0.015, 0.

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer's Disease.

Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer's disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants () ranging between 0.075 and 25 µM.

Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents.

The fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pK of the oxime group (fluorinated < chlorinated < non-halogenated) along with higher level of oximate anion formation at the physiological pH, and had a higher binding affinity of both AChE and BChE. The stability tests showed that the fluorinated oximes were stable in water, while in buffered environment di-fluorinated oximes were prone to rapid degradation, which was reflected in their lower reactivation ability.

Effects of low-level imidacloprid oral exposure on cholinesterase activity, oxidative stress responses, and primary DNA damage in the blood and brain of male Wistar rats.

Imidacloprid is a neonicotinoid insecticide that acts selectively as an agonist on insect nicotinic acetylcholine receptors. It is used for crop protection worldwide, as well as for non-agricultural uses. Imidacloprid systemic accumulation in food is an important source of imidacloprid exposure.

High Doses of Δ-Tetrahydrocannabinol Might Impair Irinotecan Chemotherapy: A Review of Potentially Harmful Interactions.

This review proposes the hypothesis that the effectiveness of irinotecan chemotherapy might be impaired by high doses of concomitantly administered Δ-tetrahydrocannabinol (THC). The most important features shared by irinotecan and THC, which might represent sources of potentially harmful interactions are: first-pass hepatic metabolism mediated by cytochrome P450 (CYP) enzyme CYP3A4; glucuronidation mediated by uridine diphosphate glycosyltransferase (UGT) enzymes, isoforms 1A1 and 1A9; transport of parent compounds and their metabolites via canalicular ATP-binding cassette (ABC) transporters ABCB1 and ABCG2; enterohepatic recirculation of both parent compounds, which leads to an extended duration of their pharmacological effects; possible competition for binding to albumin; butyrylcholinesterase (BChE) inhibition by THC, which might impair the conversion of parent irinotecan into the SN-38 metabolite; mutual effects on mitochondrial dysfunction and induction of oxidative stress; potentiation of hepatotoxicity; potentiation of genotoxicity and cytogenetic effects leading to genome instability; possible neurotoxicity; and effects on bilirubin. The controversies associated with the use of highly concentrated THC preparations with irinotecan chemotherapy are also discussed.

Evaluation of oxidative stress responses and primary DNA damage in blood and brain of rats exposed to low levels of tembotrione.

Tembotrione is a rather novel pesticide, usually used for post-emergence weed control. Even though its use is rapidly growing, it is not followed by an adequate flow of scientific evidence regarding its toxicity towards non-target organisms. We evaluated the potential of low doses of tembotrione to induce oxidative stress and cytogenetic damage in blood and brain cells of adult male Wistar rats.

Pharmacokinetic Evaluation of Brain Penetrating Morpholine-3-hydroxy-2-pyridine Oxime as an Antidote for Nerve Agent Poisoning.

Nerve agents, the deadliest chemical warfare agents, are potent inhibitors of acetylcholinesterase (AChE) and cause rapid cholinergic crisis with serious symptoms of poisoning. Oxime reactivators of AChE are used in medical practice in the treatment of nerve agent poisoning, but the search for novel improved reactivators with central activity is an ongoing pursuit. For numerous oximes synthesized, reactivation is a standard approach in biological evaluation with little attention given to the pharmacokinetic properties of the compounds.

DNA Damaging Effects, Oxidative Stress Responses and Cholinesterase Activity in Blood and Brain of Wistar Rats Exposed to Δ-Tetrahydrocannabinol.

Currently we are faced with an ever-growing use of Δ-tetrahydrocannabinol (THC) preparations, often used as supportive therapies for various malignancies and neurological disorders. As some of illegally distributed forms of such preparations, like cannabis oils and butane hash oil, might contain over 80% of THC, their consumers can become intoxicated or experience various detrimental effects. This fact motivated us for the assessments of THC toxicity in vivo on a Wistar rat model, at a daily oral dose of 7 mg/kg which is comparable to those found in illicit preparations.

Reversal of Tabun Toxicity Enabled by a Triazole-Annulated Oxime Library-Reactivators of Acetylcholinesterase.

Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge.

Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure.

In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously employed in terrorism, the alkylpyridinium aldoximes have received primary attention since their early development by I. B. Wilson in the 1950s.

Oxidative stress in triazine pesticide toxicity: a review of the main biomarker findings.

This review article provides a summary of the studies relying on oxidative stress biomarkers (lipid peroxidation and antioxidant enzymes in particular) to investigate the effects of atrazine and terbuthylazine exposure in experimental animals and humans published since 2010. In general, experimental animals showed that atrazine and terbuthylazine exposure mostly affected their antioxidant defences and, to a lesser extent, lipid peroxidation, but the effects varied by the species, sex, age, herbicide concentration, and duration of exposure. Most of the studies involved aquatic organisms as useful and sensitive bio-indicators of environmental pollution and important part of the food chain.

Oxidative stress, cholinesterase activity, and DNA damage in the liver, whole blood, and plasma of Wistar rats following a 28-day exposure to glyphosate.

In this 28 day-study, we evaluated the effects of herbicide glyphosate administered by gavage to Wistar rats at daily doses equivalent to 0.1 of the acceptable operator exposure level (AOEL), 0.5 of the consumer acceptable daily intake (ADI), 1.

Irinotecan and Δ⁸-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary Evaluation Using Biochemical and Genotoxicity Markers.

There is growing interest regarding the use of herbal preparations based on for medicinal purposes, despite the poorly understood interactions of their main constituent Δ⁸-tetrahydrocannabinol (THC) with conventional drugs, especially cytostatics. The objective of this pilot study was to prove whether the concomitant intake of THC impaired liver function in male Wistar rats treated with the anticancer drug irinotecan (IRI), and evaluate the toxic effects associated with this exposure. IRI was administered once intraperitoneally (at 100 mg/kg of the body weight (b.

Effects of the chloro-s-triazine herbicide terbuthylazine on DNA integrity in human and mouse cells.

Terbuthylazine belongs to the chloro-s-triazine group of herbicides and acts primarily as a photosynthesis inhibitor. The mechanisms of action related to its exposure, relevant both in animals and humans, are still insufficiently investigated. This comprehensive study focused on the outcomes of terbuthylazine exposure at cell level in vitro, and a mice model in vivo.

Evaluation of chlorpyrifos toxicity through a 28-day study: Cholinesterase activity, oxidative stress responses, parent compound/metabolite levels, and primary DNA damage in blood and brain tissue of adult male Wistar rats.

In this 28 day-study, we evaluated the effects of the insecticide chlorpyrifos orally administered to Wistar rats at doses 0.160, 0.015, and 0.

Effects of sub-chronic exposure to terbuthylazine on DNA damage, oxidative stress and parent compound/metabolite levels in adult male rats.

Terbuthylazine is a selective pre- and post-emergency chloro-triazine herbicide used for a broad spectrum of weed control. We evaluated the potential of low doses of terbuthylazine to induce oxidative stress and cytogenetic damage in peripheral blood samples of adult male Wistar rats. Following 28-day repeated oral exposure at 0.

Effects of low doses of glyphosate on DNA damage, cell proliferation and oxidative stress in the HepG2 cell line.

We studied the toxic effects of glyphosate in vitro on HepG2 cells exposed for 4 and 24 h to low glyphosate concentrations likely to be encountered in occupational and residential exposures [the acceptable daily intake (ADI; 0.5 μg/mL), residential exposure level (REL; 2.91 μg/mL) and occupational exposure level (OEL; 3.

A comprehensive evaluation of novel oximes in creation of butyrylcholinesterase-based nerve agent bioscavengers.

A well-considered treatment of acute nerve agents poisoning involves the exogenous administration of butyrylcholinesterase (BChE, EC 3.1.1.

Cytotoxic, genotoxic and biochemical markers of insecticide toxicity evaluated in human peripheral blood lymphocytes and an HepG2 cell line.

This study evaluated the cyto- and genotoxic effects of three pesticides: α-cypermethrin, chlorpyrifos and imidacloprid applied in vitro to human lymphocytes and HepG2 cells for exposure times of 4 and 24 h at concentrations corresponding to OEL, ADI and REL. Assessments were made using oxidative stress biomarkers and the alkaline comet, cytokinesis-block micronucleus cytome and cell viability assays. Low doses of all three pesticides displayed DNA damaging potential, both in lymphocytes and HepG2 cells.