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Epilepsy Research Sep 2023Studies conducted in recent years have indicated a relationship between epilepsy and gut microbiota. Ion channels, excitatory/inhibitory balance and regulatory systems...
Studies conducted in recent years have indicated a relationship between epilepsy and gut microbiota. Ion channels, excitatory/inhibitory balance and regulatory systems play a role in the pathophysiology of epilepsy. In addition, gut dysbiosis is also involved in the pathophysiology of epilepsy. This research investigated the impacts of probiotic mixture on epileptic seizures, Gamma aminobutyric acid (GABA), glutamate, and TAS and TOS levels in hippocampal tissue in the PTZ-induced acute seizure model in rats. Four groups were formed with male Wistar albino rats. The first and second groups were given 1 ml/day saline solution, and the other groups were given 0.05 mg/1 ml/day vehicle or 10cfu/1 ml/day probiotic supplementation, respectively via gavage for 21 days. A single-dose PTZ (45 mg/kg) was administered to induce seizure. The stages of seizure were analyzed according to the Racine scale. While ELISA was used to determine GABA and glutamate levels in the hippocampus, an automated colorimetric method was utilized to measure oxidant/antioxidant biomarkers. It was found that by delaying the first myoclonic jerk (FMJ), and the onset of the generalized tonic-clonic seizures, the probiotic mixture demonstrated anticonvulsant effects against seizures. The probiotic mixture was found to increase the inhibitory neurotransmitter GABA. It was also found to decrease TOS levels and increase TAS concentration. The findings of this study showed that probiotic mixture reduced oxidative stress with its positive effects against PTZ-induced epileptic seizures. Further studies are needed to reveal potentially related mechanisms.
Topics: Rats; Male; Animals; Glutamic Acid; Rats, Wistar; Pentylenetetrazole; Seizures; Epilepsy; gamma-Aminobutyric Acid; Anticonvulsants; Oxidative Stress; Probiotics
PubMed: 37473590
DOI: 10.1016/j.eplepsyres.2023.107190 -
Chemico-biological Interactions Dec 2023Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of...
Based on previous finding showing 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indole as suitable scaffold of novel inhibitors of acetylcholinesterase (AChE), a main target of drugs for the treatment of Alzheimer's disease and related dementias, herein we investigated diverse newly and previously synthesized β-enamino esters (and ketones) derivatives of 1,4,7,8-tetrahydroazocines (and some azonines) fused with benzene, 1H-indole, 4H-chromen-4-one and pyrimidin-4(3H)-one. Twenty derivatives of diversely annelated eight-to-nine-membered azaheterocyclic ring, prepared through domino reaction of the respective tetrahydropyridine and azepine with activated alkynes, were assayed for the inhibitory activity against AChE and butyrylcholinesterase (BChE). As a major outcome, compound 7c, an alkylamino derivative of tetrahydropyrimido[4,5-d]azocine, was found to be a highly potent BChE-selective inhibitor, which showed a noncompetitive/mixed-type inhibition mechanism against human BChE with single digit nanomolar inhibition constant (K = 7.8 ± 0.2 nM). The four-order magnitude BChE-selectivity of 7c clearly reflects the effect of lipophilicity upon binding to the BChE binding cavity. The ChEs' inhibition data, interpreted by chemoinformatic tools and an in-depth in-silico study (molecular docking combined with molecular dynamics calculations), not only highlighted key structural factors enhancing inhibition potency and selectivity toward BChE, but also shed light on subtle differences distinguishing the binding sites of equine BChE from the recombinant human BChE. Compound 7c inhibited P-glycoprotein with IC of 0.27 μM, which may support its ability to permeate blood-brain barrier, and proved to be no cytotoxic in human liver cancer cell line (HepG2) at the BChE bioactive concentrations. Overall, the biological profile allows us to envision 7c as a promising template to improve design and development of BChE-selective ligands of pharmaceutical interest, including inhibitors and fluorogenic probes.
Topics: Animals; Humans; Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Esters; Indoles; Molecular Docking Simulation; Structure-Activity Relationship
PubMed: 37839515
DOI: 10.1016/j.cbi.2023.110741 -
Environmental Pollution (Barking, Essex... Jul 2023The massive generation of synthetic textile waste has drawn considerable attention. Landfilling/incineration of textile waste has been widely made. To abate the...
The massive generation of synthetic textile waste has drawn considerable attention. Landfilling/incineration of textile waste has been widely made. To abate the environmental burdensome from the conventional management processes, a thermo-catalytic conversion was used for rapid volume reduction of textile waste and simultaneous valorization by recovering textile monomer in this study. Stockings were chosen as a model feedstock. Because stockings consisted of nylon with other contents, different products (caprolactam (nylon monomer), imines, cyclic dimers, and azepines) were recovered. The yield of caprolactam from the thermal conversion at 500 °C was 53.6 wt%. To selectively enhance the caprolactam yield, catalytic pyrolysis was done using γ-AlO supported metal catalysts (Ni, Cu, Fe, or Co). γ-AlO itself increased the caprolactam yield up to 69.0 wt% via a based-catalyzed reaction of nylon depolymerization and intramolecular cyclization. Under the presence of metal catalysts, the caprolactam yield increased up to 73.3 wt%. To offer desired feature of green chemistry, CO was adopted as reactive gas. Under the CO-mediated catalytic pyrolysis, caprolactam yield was enhanced up to 77.1 wt% over Cu/AlO (basis: stocking mass). Based on the net content of nylon in the stockings, the yield of caprolactam was deemed 95.3 wt%. This study proves that textile waste (stocking) and CO are useful resources for recovery of nylon monomer, which can reduce the waste generation with simultaneous recovery of value-added product.
Topics: Nylons; Caprolactam; Carbon Dioxide; Textiles; Metals; Catalysis
PubMed: 37087088
DOI: 10.1016/j.envpol.2023.121684 -
Biomedicine & Pharmacotherapy =... Mar 2024Previously, we demonstrated that palmatine (PALM) - an isoquinoline alkaloid from Berberis sibrica radix, exerted antiseizure activity in the pentylenetetrazole...
Previously, we demonstrated that palmatine (PALM) - an isoquinoline alkaloid from Berberis sibrica radix, exerted antiseizure activity in the pentylenetetrazole (PTZ)-induced seizure assay in larval zebrafish. The aim of the present study was to more precisely characterize PALM as a potential anticonvulsant drug candidate. A range of zebrafish and mouse seizure/epilepsy models were applied in the investigation. Immunostaining analysis was conducted to assess the changes in mouse brains, while in silico molecular modelling was performed to determine potential targets for PALM. Accordingly, PALM had anticonvulsant effect in ethyl 2-ketopent-4-enoate (EKP)-induced seizure assay in zebrafish larvae as well as in the 6 Hz-induced psychomotor seizure threshold and timed infusion PTZ tests in mice. The protective effect in the EKP-induced seizure assay was confirmed in the local field potential recordings. PALM did not affect seizures in the gabra1a knockout line of zebrafish larvae. In the scn1Lab zebrafish line, pretreatment with PALM potentiated seizure-like behaviour of larvae. Repetitive treatment with PALM, however, did not reduce development of PTZ-induced seizure activity nor prevent the loss of parvalbumin-interneurons in the hippocampus of the PTZ kindled mice. In silico molecular modelling revealed that the noted anticonvulsant effect of PALM in EKP-induced seizure assay might result from its interactions with glutamic acid decarboxylase and/or via AMPA receptor non-competitive antagonism. Our study has demonstrated the anticonvulsant activity of PALM in some experimental models of seizures, including a model of pharmacoresistant seizures induced by EKP. These results indicate that PALM might be a suitable new drug candidate but the precise mechanism of its anticonvulsant activity has to be determined.
Topics: Mice; Animals; Anticonvulsants; Zebrafish; Seizures; Epilepsy; Pentylenetetrazole; Berberine Alkaloids
PubMed: 38325264
DOI: 10.1016/j.biopha.2024.116234 -
PloS One 2023A common way to investigate epilepsy and the effect of antiepileptic pharmaceuticals is to analyze the movement patterns of zebrafish larvae treated with different...
A common way to investigate epilepsy and the effect of antiepileptic pharmaceuticals is to analyze the movement patterns of zebrafish larvae treated with different convulsants like pentylenetetrazol (PTZ), pilocarpine, etc. Many articles have been written on this topic, but the research methods and exact settings are not sufficiently defined in most. Here we designed and executed a series of experiments to optimize and standardize the zebrafish epilepsy model. We found that during the light and the dark trials, the zebrafish larvae moved significantly more in the light, independent of the treatment, both in PTZ and pilocarpine-treated and the control groups. As expected, zebrafish larvae treated with convulsants moved significantly more than the ones in the control group, although this difference was higher between the individuals treated with PTZ than pilocarpine. When examining the optimal observation time, we divided the half-hour period into 5-minute time intervals, and between these, the first 5 minutes were found to be the most different from the others. There were fewer significant differences in the total movement of larvae between the other time intervals. We also performed a linear regression analysis with the cumulative values of the distance moved during the time intervals that fit the straight line. In conclusion, we recommend 30 minutes of drug pretreatment followed by a 10-minute test in light conditions with a 5-minute accommodation time. Our result paves the way toward improved experimental designs using zebrafish to develop novel pharmaceutical approaches to treat epilepsy.
Topics: Animals; Pentylenetetrazole; Zebrafish; Convulsants; Pilocarpine; Larva; Epilepsy; Anticonvulsants; Disease Models, Animal
PubMed: 37506089
DOI: 10.1371/journal.pone.0288904 -
Nigerian Journal of Physiological... Dec 2023Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions....
Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions. Therefore, there is need for new therapeutic intervention that will prevent epileptogenesis with greater therapeutic success. Quercetin (QT) is a flavonoid with known neuroprotective and anti-inflammatory properties. The study aimed to investigate its effects against pentylenetetrazole (PTZ)-induced seizures. Animals were divided into four groups (n = 10). Group 1(control) only received vehicle (10 mL/kg), group 2 received vehicle, groups 3 and 4 received QT 12.5 mg/kg and 25 mg/kg respectively. Sixty minutes after treatments, animals in groups 2 to 4 were injected with sub-convulsive dose of pentylenetetrazole (35 mg/kg, i.p.) on every alternate day (48±2h) for 21 days. The mice were observed for 30 minutes after each PTZ injection for seizure activity. Brain samples were collected for biochemical assays. Administration of PTZ caused significant increase in the intensity of seizures, neuronal degeneration and level of proinflammatory cytokines in animals compared to control. These behavioural alterations were attenuated significantly by QT (12.5 and 25 mg/kg). The PTZ-induced increase in IL-12, TNF-α and IFN-ɣ were significantly reduced by pre-treatment with the QT (12.5 and 25 mg/kg, p.o). Quercetin also reduced neuronal loss compared to control. Quercetin attenuates seizures in kindled mice and reduces neuroinflammation and neurodegeneration. This neuroprotective effect may be attributed to its ability to inhibit inflammatory mediators in the brain.
Topics: Animals; Quercetin; Pentylenetetrazole; Seizures; Mice; Anticonvulsants; Male; Neuroinflammatory Diseases; Cytokines; Disease Models, Animal; Brain; Neuroprotective Agents; Anti-Inflammatory Agents
PubMed: 38696687
DOI: 10.54548/njps.v38i2.7 -
International Journal of Molecular... Aug 2023Epilepsy is characterized by recurrent seizures due to a perturbed balance between glutamate and GABA neurotransmission. Our goal is to reveal the molecular mechanisms...
Pentylenetetrazole-Induced Seizures Are Increased after Kindling, Exhibiting Vitamin-Responsive Correlations to the Post-Seizures Behavior, Amino Acids Metabolism and Key Metabolic Regulators in the Rat Brain.
Epilepsy is characterized by recurrent seizures due to a perturbed balance between glutamate and GABA neurotransmission. Our goal is to reveal the molecular mechanisms of the changes upon repeated challenges of this balance, suggesting knowledge-based neuroprotection. To address this goal, a set of metabolic indicators in the post-seizure rat brain cortex is compared before and after pharmacological kindling with pentylenetetrazole (PTZ). Vitamins B1 and B6 supporting energy and neurotransmitter metabolism are studied as neuroprotectors. PTZ kindling increases the seizure severity (1.3 fold, < 0.01), elevating post-seizure rearings (1.5 fold, = 0.03) and steps out of the walls (2 fold, = 0.01). In the kindled vs. non-kindled rats, the post-seizure p53 level is increased 1.3 fold ( = 0.03), reciprocating a 1.4-fold ( = 0.02) decrease in the activity of 2-oxoglutarate dehydrogenase complex (OGDHC) controlling the glutamate degradation. Further, decreased expression of deacylases SIRT3 (1.4 fold, = 0.01) and SIRT5 (1.5 fold, = 0.01) reciprocates increased acetylation of 15 kDa proteins 1.5 fold ( < 0.01). Finally, the kindling abrogates the stress response to multiple saline injections in the control animals, manifested in the increased activities of the pyruvate dehydrogenase complex, malic enzyme, glutamine synthetase and decreased malate dehydrogenase activity. Post-seizure animals demonstrate correlations of p53 expression to the levels of glutamate (r = 0.79, = 0.05). The correlations of the seizure severity and duration to the levels of GABA (r = 0.59, = 0.05) and glutamate dehydrogenase activity (r = 0.58, = 0.02), respectively, are substituted by the correlation of the seizure latency with the OGDHC activity (r = 0.69, < 0.01) after the vitamins administration, testifying to the vitamins-dependent impact of the kindling on glutamate/GABA metabolism. The vitamins also abrogate the correlations of behavioral parameters with seizure duration (r 0.53-0.59, < 0.03). Thus, increased seizures and modified post-seizure behavior in rats after PTZ kindling are associated with multiple changes in the vitamin-dependent brain metabolism of amino acids, linked to key metabolic regulators: p53, OGDHC, SIRT3 and SIRT5.
Topics: Rats; Animals; Pentylenetetrazole; Vitamins; Sirtuin 3; Tumor Suppressor Protein p53; Seizures; Amino Acids; Glutamic Acid; Brain; gamma-Aminobutyric Acid
PubMed: 37569781
DOI: 10.3390/ijms241512405 -
Bioorganic Chemistry Feb 2024Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short-chain hemorphin peptide analogs containing non-natural amino acids....
Synthesis, molecular docking, electrochemical and fluorimetric analysis of new caffeic and cinnamic acid-conjugated hemorphin derivatives designed as potential anticonvulsant and antinociceptive agents.
Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short-chain hemorphin peptide analogs containing non-natural amino acids. They demonstrated anticonvulsant and antinociceptive activity with low neurotoxicity. In the present study, a series of novel bioconjugates of N-modified hemorphin analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetric analysis, in vivo anticonvulsant and antinociceptive activity in mice were conducted on the compounds. The three CA acid- (H4-CA, H5-CA, and H7-CA) and three KA acid- (H4-KA, H5-KA, and H7-KA) conjugated hemorphin derivatives exhibited potency at the highest doses of 2 µg/5 µl, administered by intracerebroventricular (icv) mode, against seizure spread in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate, at the lowest dose, was the only compound that suppressed clonic seizures in the subcutaneous pentylenetetrazol (scPTZ) test. Except for the H5-CA, all tested CA acid- and KA acid-conjugated peptide derivates had the potency to increase the latency for clonic seizures in a dose-dependent mode. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. All investigated peptides showed a more pronounced antinociceptive effect in the "intraplantar formalin" test compared to the "hot plate" test. Shorter chain analogs showed a better antinociceptive profile against tonic pain. The data suggest a DOR and KOR-mediated mechanism of action. According to the docking analysis, H7-CA showed a different antinociceptive profile than other investigated peptides. The novel peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA morphine peptides can be used to develop novel morphine-related analogs with anticonvulsant and antinociceptive activity.
Topics: Mice; Animals; Anticonvulsants; Molecular Docking Simulation; Seizures; Pentylenetetrazole; Analgesics; Electroshock; Peptides; Morphine Derivatives; Cinnamates
PubMed: 38150935
DOI: 10.1016/j.bioorg.2023.107063 -
The Journal of Organic Chemistry Dec 2023Inversion barriers Δ for planar chiral phosphine-alkene and sulfonamide-alkene hybrid ligands based on phenyl-dibenz[]azepine have been determined by density-functional...
Inversion barriers Δ for planar chiral phosphine-alkene and sulfonamide-alkene hybrid ligands based on phenyl-dibenz[]azepine have been determined by density-functional theory calculations. Analysis of the structural and electronic characteristics of the minima and transition states explains the magnitudes of Δ and the geometrical changes during the inversion process. The steric repulsion caused by bulky substituents attached to the azepine nitrogen atom has a pronounced effect on the Δ value, explaining, inter alia, the stereochemical stability of the P- and S-alkene ligands when compared to the fluxional parent compound where X = H.
PubMed: 37944159
DOI: 10.1021/acs.joc.3c01447 -
Water Science and Technology : a... Nov 2023In this study, wet oxidation of excess sludge from the caprolactam wastewater treatment process was investigated. The effects of reaction conditions, including sludge...
In this study, wet oxidation of excess sludge from the caprolactam wastewater treatment process was investigated. The effects of reaction conditions, including sludge concentration, the amount of sludge, reaction temperature and time and the oxygen supply amount, were discussed. The highest removal rates of chemical oxygen demand (COD) and volatile suspended solid (VSS) that can be attained at 78.6 and 89.3% were acquired separately under 260 °C for 60 min with an initial oxygen gas pressure of 1.3 MPa. The sludge was hydrolyzed and oxidized under hydrothermal conditions, producing small molecule organic acids, such as acetic, formic and oxalic acids, as the main products, which could be used as carbon sources for wastewater treatment. These results indicated that wet oxidation provides a favourable and feasible alternative method for the treatment of excess sludge from the coal chemical industry.
Topics: Sewage; Caprolactam; Waste Disposal, Fluid; Oxidation-Reduction; Water Purification; Biological Oxygen Demand Analysis; Oxygen
PubMed: 38017673
DOI: 10.2166/wst.2023.366