-
Pharmaceuticals (Basel, Switzerland) Jun 2024Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding...
The Influence of an Acute Administration of Cannabidiol or Rivastigmine, Alone and in Combination, on Scopolamine-Provoked Memory Impairment in the Passive Avoidance Test in Mice.
Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor-scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated.
PubMed: 38931476
DOI: 10.3390/ph17060809 -
Molecules (Basel, Switzerland) Jun 2024Aubl. is widely available in the market as traditional Chinese medicine and animal feed, due to its properties of clearing heat and treating malaria and its...
Aubl. is widely available in the market as traditional Chinese medicine and animal feed, due to its properties of clearing heat and treating malaria and its high-protein and crude fiber content. In this study, the essential oil of was obtained through hydrodistillation. GC-MS and GC-FID methods were used to identify the chemical components and their relative abundance. Furthermore, the antioxidant capacity was measured using DPPH, ABTS, and FRAP assays, and the inhibitory effects of acetylcholinesterase, α-glucosidase, and β-lactamase were also evaluated. A total of 67 compounds were identified, with the major constituents being palmitic acid (30.74%), linoleic acid (16.13%), and phenylheptatriyne (8.07%). The essential oil exhibited moderate antioxidant activity against DPPH (IC > 10 mg/mL), while the IC value for the ABTS assay was 3.84 ± 2.12 mg/mL and the FRAP assay value was 87.22 ± 12.22 µM/g. Additionally, the essential oil showed moderate anti-acetylcholinesterase activity (IC = 286.0 ± 79.04 μg/mL), significant anti-α-glucosidase activity (IC = 174.7 ± 13.12 μg/mL), and potent anti-β-lactamase activity (IC = 37.56 ± 3.48 μg/mL). The results suggest that has the potential for application in pharmacology, warranting further exploration and investigation.
Topics: Oils, Volatile; Antioxidants; beta-Lactamases; Acetylcholinesterase; Cholinesterase Inhibitors; Glycoside Hydrolase Inhibitors; alpha-Glucosidases
PubMed: 38930934
DOI: 10.3390/molecules29122869 -
Medicina (Kaunas, Lithuania) Jun 2024The focus on mild cognitive dysfunction in adults is of great interest, given the risk of worsening and conversion to dementia. Cognitive dysfunctions are characterized... (Randomized Controlled Trial)
Randomized Controlled Trial
The focus on mild cognitive dysfunction in adults is of great interest, given the risk of worsening and conversion to dementia. Cognitive dysfunctions are characterized by a decrease in the weight and volume of the brain, due to cortical atrophy, with a widening of the grooves and flattening of the convolutions. Brain atrophy that mainly involves the hippocampus is related to the progression of cognitive impairment and the conversion from mild cognitive dysfunction to dementia. Currently, there is no treatment for MCI. Results from a trial on Alzheimer's disease (ASCOMALVA trial) suggest that a sustained cholinergic challenge can slow the progression of brain atrophy typical of Alzheimer's disease associated with vascular damage. This study intends to evaluate the efficacy of choline alphoscerate in patients with mild cognitive impairment (MCI) and associated vascular damage, in stabilizing and/or slowing brain atrophy typical of adult-onset cognitive dysfunction, and in improving and/or slowing the progression of cognitive and behavioral symptoms associated with MCI. : This randomized controlled trial will recruit 60 patients that will be evaluated and randomized in a 1:1 ratio to receive choline alphoscerate (1200 mg/day) or placebo, for 12 months. Analyses will be carried out using SPSS vesion No 26 the Statistician in charge of this study, with the statistical significance level chosen as 0.05. : This trial may provide evidence about the efficacy of treatment with the cholinergic precursor choline alphoscerate in patients with mild cognitive dysfunction. The results of this study will be published in peer-reviewed journals. EudraCT number: 2020-000576-38.
Topics: Humans; Cognitive Dysfunction; Glycerylphosphorylcholine; Male; Female; Aged; Middle Aged; Cholinergic Agents; Randomized Controlled Trials as Topic
PubMed: 38929542
DOI: 10.3390/medicina60060925 -
International Journal of Environmental... Jun 2024The emerging concern about chemicals in electronic cigarettes, even those without nicotine, demands the development of advanced criteria for their exposure and risk...
The emerging concern about chemicals in electronic cigarettes, even those without nicotine, demands the development of advanced criteria for their exposure and risk assessment. This study aims to highlight the sensitivity of lung nuclear receptors (NRs) to electronic cigarette e-liquids, independent of nicotine presence, and the influence of the sex variable on these effects. Adult male and female C57BL/6J mice were exposed to electronic cigarettes with 0%, 3%, and 6% nicotine daily (70 mL, 3.3 s, 1 puff per min/30 min) for 14 days, using the inExpose full body chamber (SCIREQ). Following exposure, lung tissues were harvested, and RNA extracted. The expression of 84 NRs was determined using the RT profiler mRNA array (Qiagen). Results exhibit a high sensitivity to e-liquid exposure irrespective of the presence of nicotine, with differential expression of NRs, including one (females) and twenty-four (males) in 0% nicotine groups compared to non-exposed control mice. However, nicotine-dependent results were also significant with seven NRs (females), fifty-three NRs (males) in 3% and twenty-three NRs (female) twenty-nine NRs (male) in 6% nicotine groups, compared to 0% nicotine mice. Sex-specific changes were significant, but sex-related differences were not observed. The study provides a strong rationale for further investigation.
Topics: Animals; Female; Male; Electronic Nicotine Delivery Systems; Mice, Inbred C57BL; Pilot Projects; Mice; Lung; Aerosols; Nicotine; Receptors, Cytoplasmic and Nuclear; Sex Factors
PubMed: 38929056
DOI: 10.3390/ijerph21060810 -
International Journal of Molecular... Jun 2024The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of...
The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of accelerated electron radiation on some pivotal neurotransmitter circuits (cholinergic and serotonergic) of rats' myenteric plexus. Male Wistar rats were irradiated with an electron beam (9 MeV, 5 Gy) generated by a multimodality linear accelerator. The contractile activity of isolated smooth muscle samples from the gastric corpus was measured. Furthermore, an electrical stimulation (200 μs, 20 Hz, 50 s, 60 V) was performed on the samples and an assessment of the cholinergic and serotonergic circuits was made. Five days after irradiation, the recorded mechanical responses were biphasic-contraction/relaxation in controls and contraction/contraction in irradiated samples. The nature of the contractile phase of control samples was cholinergic with serotonin involvement. The relaxation phase involved ACh-induced nitric oxide release from gastric neurons. There was a significant increase in serotonergic involvement during the first and second contractile phases of the irradiated samples, along with a diminished role of acetylcholine in the first phase. This study demonstrates an increased involvement of serotonergic neurotransmitter circuits in the gastric myenteric plexus caused by radiation with accelerated electrons.
Topics: Animals; Myenteric Plexus; Male; Rats; Rats, Wistar; Stomach; Electrons; Muscle, Smooth; Serotonin; Muscle Contraction; Acetylcholine; Nitric Oxide
PubMed: 38928511
DOI: 10.3390/ijms25126807 -
International Journal of Molecular... Jun 2024Chlorpyrifos (CPF) is a widely used organophosphate insecticide, though its excessive use causes environmental contamination, raising concerns about its adverse effects...
Chlorpyrifos (CPF) is a widely used organophosphate insecticide, though its excessive use causes environmental contamination, raising concerns about its adverse effects on human health. In this regard, stands out as a promising candidate for counteracting chemical 'contaminant' toxicity thanks to its therapeutic properties. Therefore, our study aimed to investigate the potential of an ethanolic extract (UDE) to mitigate chlorpyrifos-induced toxicity. Eight compounds in the ethanolic extract have been identified, most of which present significant potential as antioxidant, anti-inflammatory, and neuroprotective agents. Chlorpyrifos exposure altered hatching rates, increased the incidence of teratogenic effects, and upregulated the expression of brain-derived neurotrophic factor (Bdnf) in zebrafish larvae telencephalon. On the other hand, demonstrated a preventive effect against CPF-induced teratogenicity, which is expressed by a lower morphological deformity rate. Moreover, the UDE showed a rather protective effect, maintaining the physiological condition of the telencephalon. Additionally, CPF altered the locomotor behavior of larvae, which was characterized by irregular swimming and increased activity. This defective behavioral pattern was slightly attenuated by the UDE. Our findings suggest that the UDE possesses significant protective properties against CPF-induced toxicity, probably conferred by its natural antioxidant and anti-inflammatory contents. Still, further research is needed to elucidate the recruited mechanisms and implicated pathways on UDE's protective effects.
Topics: Animals; Zebrafish; Chlorpyrifos; Plant Extracts; Larva; Urtica dioica; Antioxidants; Insecticides; Telencephalon
PubMed: 38928336
DOI: 10.3390/ijms25126631 -
International Journal of Molecular... Jun 2024Opinions on the effects of osteoprotegerin (OPG) have evolved over the years from a protein protecting the vasculature from calcification to a cardiovascular risk factor...
Opinions on the effects of osteoprotegerin (OPG) have evolved over the years from a protein protecting the vasculature from calcification to a cardiovascular risk factor contributing to inflammation within the vascular wall. Nowadays, the link between OPG and angiotensin II (Ang II) appears to be particularly important. In this study, the endothelial function was investigated in OPG-knockout mice (B6.129.S4-OPG, OPG) and wild-type (C57BL/6J, OPG) mice under basic conditions and after Ang II exposure by assessing the endothelium-dependent diastolic response of aortic rings to acetylcholine in vitro. A further aim of the study was to compare the effect of Ang II on the expression of cytokines in the aortic wall of both groups of mice. Our study shows that rings from OPG mice had their normal endothelial function preserved after incubation with Ang II, whereas those from OPG mice showed significant endothelial dysfunction. We conclude that the absence of OPG, although associated with a pro-inflammatory cytokine profile in the vascular wall, simultaneously protects against Ang II-induced increases in pro-inflammatory cytokines in the murine vascular wall. Our study also demonstrates that the absence of OPG can result in a decrease in the concentration of pro-inflammatory cytokines in the vascular wall after Ang II exposure. The presence of OPG is therefore crucial for the development of Ang II-induced inflammation in the vascular wall and for the development of Ang II-induced endothelial dysfunction.
Topics: Animals; Angiotensin II; Osteoprotegerin; Mice; Endothelium, Vascular; Mice, Knockout; Mice, Inbred C57BL; Cytokines; Male; Aorta; Acetylcholine
PubMed: 38928140
DOI: 10.3390/ijms25126434 -
International Journal of Molecular... Jun 2024Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful...
Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful synthesis of the dual binding femtomolar triazole inhibitor of acetylcholinesterase (AChE, EC 3.1.1.7) by Sharpless et al. via click chemistry. Here, we evaluate the anticholinesterase effect of the first isopropanol triazole fungicide mefentrifluconazole (Ravystar), developed to overcome fungus resistance in plant disease management. Mefentrifluconazole is commercially available individually or in a binary fungicidal mixture, i.e., with pyraclostrobin (Ravycare). Pyraclostrobin is a carbamate that contains a pyrazole ring. Carbamates are known inhibitors of cholinesterases and the carbamate rivastigmine is already in use for the treatment of Alzheimer's disease. We tested the type and potency of anticholinesterase activity of mefentrifluconazole and pyraclostrobin. Mefentrifluconazole reversibly inhibited human AChE and BChE with a seven-fold higher potency toward AChE ( = 101 ± 19 μM). Pyraclostrobin (50 μM) inhibited AChE and BChE progressively with rate constants of (t = 2.1 min; = 6.6 × 10 M min) and (t = 1.5 min; = 9.2 × 10 M min), respectively. A molecular docking study indicated key interactions between the tested fungicides and residues of the lipophilic active site of AChE and BChE. Additionally, the physicochemical properties of the tested fungicides were compared to values for CNS-active drugs to estimate the blood-brain barrier permeability. Our results can be applied in the design of new molecules with a lesser impact on humans and the environment.
Topics: Strobilurins; Cholinesterase Inhibitors; Acetylcholinesterase; Humans; Fungicides, Industrial; Triazoles; Molecular Docking Simulation; Butyrylcholinesterase; Pyrazoles
PubMed: 38928014
DOI: 10.3390/ijms25126310 -
Biomolecules Jun 2024Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and...
Alterations in mitochondrial function have been linked to a variety of cellular and organismal stress responses including apoptosis, aging, neurodegeneration and tumorigenesis. However, adaptation to mitochondrial dysfunction can occur through the activation of survival pathways, whose mechanisms are still poorly understood. The yeast is an invaluable model organism for studying how mitochondrial dysfunction can affect stress response and adaptation processes. In this study, we analyzed and compared in the absence and in the presence of osmostress wild-type cells with two models of cells lacking mitochondrial DNA: ethidium bromide-treated cells (ρ) and cells lacking the mitochondrial pyrimidine nucleotide transporter (Δ). Our results revealed that the lack of mitochondrial DNA provides an advantage in the kinetics of stress response. Additionally, wild-type cells exhibited higher osmosensitivity in the presence of respiratory metabolism. Mitochondrial mutants showed increased glycerol levels, required in the short-term response of yeast osmoadaptation, and prolonged oxidative stress. The involvement of the mitochondrial retrograde signaling in osmoadaptation has been previously demonstrated. The expression of , encoding the peroxisomal isoform of citrate synthase and whose up-regulation is prototypical of RTG pathway activation, appeared to be increased in the mutants. Interestingly, selected TCA cycle genes, and , whose expression depends on RTG signaling upon stress, showed a different regulation in ρ and Δ cells. These data suggest that osmoadaptation can occur through different mechanisms in the presence of mitochondrial defects and will allow us to gain insight into the relationships among metabolism, mitochondria-mediated stress response, and cell adaptation.
Topics: Saccharomyces cerevisiae; DNA, Mitochondrial; Saccharomyces cerevisiae Proteins; Mitochondria; Adaptation, Physiological; Oxidative Stress; Glycerol; Ethidium
PubMed: 38927107
DOI: 10.3390/biom14060704 -
Biomolecules Jun 2024New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous...
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and - [2-(()-2-(5-(()-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.
Topics: Oximes; Cholinesterase Inhibitors; Butyrylcholinesterase; Acetylcholinesterase; Humans; Triazoles; Molecular Docking Simulation; Stilbenes; Cholinesterase Reactivators; Organophosphorus Compounds; Central Nervous System
PubMed: 38927082
DOI: 10.3390/biom14060679