Anticonvulsant Activity Research Articles

The Effect of Treatment for Epilepsy Associated with Malignant Neoplasms of the Brain: a Literature Review

Introduction. Epilepsy is a frequent complication in patients with malignant neoplasms of the brain. However, despite an extensive number of studies, anticonvulsants with antitumor activity have not been studied enough. The purpose of this study was to evaluate the efficacy and tolerability of brivaracetam and levetiracetam as an additional therapy in patients with malignant brain tumors, as an anticonvulsant and antitumor agent. Materials and methods. The search was carried out in the electronic databases PubMed/MEDLINE, EMBASE, Cochrane Library until June 2023. Screening and selection of studies was carried out according to the recommendations of PRISMA. The search included a combination of queries related to “glioma”, “epilepsy”, “antiepileptic drugs” and “efficacy”. From all the relevant articles, three different results were extracted for both mono- and polytherapy: adult patients with brain malignancies; ≥55 % of patients with proven or suspected glioma using histological examination; ≥10 patients receiving the same AED. Results. The data regarding levetiracetam are contradictory. In terms of research, this drug has shown not only anticonvulsant activity, but also antitumor activity. Other researchers point to the absence of antitumor activity in levetiracitam. Brivaracetam is an effective anticonvulsant drug that has shown antitumor activity in studies, but there are not enough studies to make an adequate conclusion. Discussion. The results obtained on the antitumor activity of levetiracetam are quite contradictory. Perhaps this is due to the heterogeneity of patient populations in terms of morphological examination of the tumor, different patients receiving concomitant treatment, and the prevalence of the tumor process. With regard to brivaracetam, it is not possible to give an adequate conclusion about an effective combination of antitumor and anticonvulsant activity due to the insufficient number of studies to date. Conclusion. Levetiracetam and brivaracetam have shown high efficacy in the symptomatic treatment of epilepsy associated with brain tumors. However, data on the presence of antitumor activity in these drugs is contradictory and requires further research.

Genetic determinism of epilepsy refractoriness in patients with congenital cerebral p

Background. In the phenotype of cerebral palsy, motor and mental disorders are often accompanied by epilepsy. Congenital epilepsy has been intensively researched in recent years. Special attention is drawn to epilepsy caused by congenital disturbance of the excitability of the neuronal membrane due to canalopathies.Aim. To analyze a large number of genes associated with the development of the cerebral palsy phenotype and distribute them according to determinable traits.Materials and methods. The results of clinical and genetic analysis of 136 cases of cerebral palsy with epilepsy are presented. The patients were divided into groups according to the syndromes according to the classification of cerebral palsy. Epileptic syndromes were divided into three groups: focal childhood epilepsy with structural brain changes and benign epileptiform discharges in electroencephalogram – 41 (30.1 %) cases, structural focal epilepsy – 37 (27.2 %) cases, epileptic encephalopathies – 58 (42.7 %) cases. Pathogenic variants in genes were confirmed by next generation sequencing Sanger methods of venous blood.Results. The performed risk analysis showed that in the presence of disorders in genes attributed to the group of regulation of the formation and functioning of the cytoskeleton, the risk of lack of remission is significantly lower than in other dominants, while abnormalities in genes attributed to the group of regulation of the function of the mitochondrial apparatus significantly increase the risks of failure to achieve remission and need in polytherapy.Conclusion. Probably, the violation of energy metabolism in the cell neutralizes the stabilization of the neuronal membrane under the action of anticonvulsants. The determinant of the formation and functioning of the cytoskeleton, according to our preliminary data, is largely associated with the formation of malformations of the brain. In this case, the refractoriness of epilepsy may be secondary and determined by the severity of structural changes in the brain

Evaluation of the pharmacological profile of GABA aminotransferase inhibitor diels-alder adducts with potential anticonvulsant activity

Evaluation of the pharmacological profile of GABA aminotransferase inhibitor diels-alder adducts with potential anticonvulsant activity

A Review on Areca Catechu

Abstract: Areca catechu L.is a species of palm which grows much of tropical pacific, Asia & parts of Africa, The palm is believed to have originated in the philippines and is widely cultivated in several south Asian and Southeast Asian countries. In the present article, it Haa been describe about usefulness of Arecanut as an herbal drug and it's therapeutic application prospect Arecacatechu, commonly known as supari, consists of dried ripe nuts that came under Arecaceae family, which is cultivated in the tropical region of India and Southeast Asia. It is a prevalent traditional herbal medicine that is chewed to separate collected fluid in the alimentary canal and for killing worms. Areca catechu seed contains alkaloids (arecoline, arecaine, arecaidine, guvacoline, guvacine, and choline), tannin, gallic acid, gum, and various minerals such as copper, calcium, phosphorus, and iron. The chemical constituents of this plant have been used as antidiabetic, stomatitis, bleeding gums, gingivitis, conjunctivitis, glaucoma, leucorrhoea, urinary disorders, anorexia, diarrhea, blood pressure regulating activity, antiulcerogenic, antioxidant activity, anticonvulsant activity, central nervous system stimulant activity, antifertility, oxytocic activity, antiviral activity, anthelmintic, and making it more popular than chewing gum ,but not as popular as Tobacco.

Acute toxicity (LD50 values) and neuropharmacological profile of n-hexane fraction of Petiveria alliacea L. (Phytolaccaceae) in mice

Background: Petiveria alliacea L. (Phytolaccaceae) ethnomedically is known for its sedative property and beneficial treatment of other central nervous system (CNS) disorders. However, the neuropharmacological properties of the n-hexane extract of this aromatic plant leaf have not been reported, hence this study. Objective: To determine the acute toxicity profile (LD50) and some CNS activities of the n-hexane extract of fresh leaf of P. alliacea (NHEPA) in mice. Method: The fresh leaf of Petiveria alliacea was collected and the n-hexane extract obtained using appropriate technique. The LD50 was determined for both the oral and intraperitoneal (i.p.) route. All treatments were administered via i.p. route. Behavioural activity was evaluated using the novelty-induced behaviour (NIB) to assess rearing, grooming and locomotion; sedative activity was tested on ketamine-induced hypnosis while the anticonvulsant potential was assessed using chemo-convulsants. The mechanism of action was determined using amphetamine as agonist and flumazenil as an antagonist. Results: The LD50 values obtained for the extract was 2450 and 346 mg/kg for oral and intraperitoneal routes respectively. The extract displayed significant CNS depressant activity on all NIB parameters. NHEPA significantly prolonged sleep latency and total sleeping time at 100 and 150 mg/kg. i.p. The extract also offered some mild protection against convulsion across the model used. The probable mechanism of action may include inhibition of monoamine pathways and augmentation of the GABAA- benzodiazepine complex pathway. Conclusion: NHEPA showed CNS depressant activity, exhibited significant sedative activity and mild anticonvulsant activity.

Study of Anticonvulsant effect of Simvastatin in Maximal Electroshock and Pentylenetetrazole Induced Seizure Model In Albino Mice

Epilepsy is a common neurological condition affecting people of all ages and both sexes. Most of the currently used antiepileptic drugs have neurotoxic and teratogenic effects. There are scanty reports of anticonvulsant activity with statins. The present study was undertaken to evaluate the anticonvulsant effect of simvastatin using MES and PTZ models in mice and compare it with the standard drugs phenytoin and diazepam respectively.64 albino mice of either sex weighing 25-35g were divided into 8 groups of 8 mice each – 4 group each for MES and PTZ model. In MES model, seizures were induced via trans auricular electrodes with a current of 80mA for 0.2 second. Each mouse was pretreated with drugs 30 minutes before in both models. The different groups 1 to 4 were administered polyethylene glycol (0.5ml/Kg), phenytoin (20mg/kg), simvastatin (10mg/Kg) and simvastatin (20mg/Kg) respectively. In PTZ model, seizures were induced by giving PTZ 80mg/Kg. The different groups 5 to 8 were administered polyethylene glycol (0.5ml/Kg), diazepam (2mg/kg), simvastatin (10mg/Kg) and simvastatin (20mg/Kg) respectively. Statistical analysis was doneby ANOVA followed by Tukey’s post hoc analysis for group wise comparison. Results indicated that the anticonvulsant effect of simvastatin (10 and 20mg/Kg) was comparable to phenytoin in the MES model. In the PTZ model, simvastatin (10mg/Kg) produced a reduction in seizure duration but did not provide seizure protection as compared to that of the diazepam. The present study demonstrated the anticonvulsant effect of simvastatin. Further studies may explore the potential of this as an add-on drug in patients with dyslipidemia and epilepsy.

Exploring the neuroprotective potential of antimicrobial peptides from Dinoponera quadriceps venom against pentylenetetrazole-induced seizures in vivo

Epilepsy affects around 50 million people worldwide and 30% of patients have difficulty controlling the disease. The search for substances that can fill the existing gaps in the treatment of epilepsy is of great importance. Arthropod venoms are promising sources for this purpose due to the presence of small peptides that modulate the activity of ion channels and neuron receptors. The aim of this study was to investigate dinoponeratoxins from the Dinoponera quadriceps ant venom (M-PONTX-Dq3a, M-PONTX-Dq3b and M-PONTX-Dq3c) as potential anticonvulsants. We evaluated them in a seizure model induced by pentylenetetrazole (PTZ) in male swiss mice. Interestingly, intraperitoneal treatment with each peptide increased the time until the first seizure and the percentage of survival, with M-PONTX-Dq3b showing the best results. M-PONTX-Dq3a was discarded due to the appearance of some signs of toxicity with the increase in malondialdehyde (MDA) levels in the striatum. Both, M-PONTX-Dq3b and M-PONTX-Dq3c decreased iNOS and TNF-α in the hippocampus. Notably, M-PONTX-Dq3c treatment decreased the levels of MDA and nitrite in the cortex and hippocampus. Our results indicate that, M-PONTX-Dq3b and M-PONTX-Dq3c have anticonvulsant activity and exhibit anti-inflammatory effects in epilepsy, offering new perspectives for biopharmaceutical development.

<i>Daphnia magna Straus</i> as a Test Object for Screening Cholinergic Pharmacological Substances

Daphnia magna Straus was used as an experimental zoohydrobiont model for primary screening of compounds of the valproic acid aminoether group with anticonvulsant and cholinoblocking activity. On this basis, the most effective compounds for further trials in warm-blooded animals were selected. The selection criterion included their minimum effective concentration for the prevention of atypical motor hyperactivity induced by phenylcarbamate.

Design and synthesis of novel cycloalkanecarboxamide parabanic acid hybrids as anticonvulsants

Aiming to develop novel anticonvulsant agents a new series of novel cycloalkanecarboxamide parabanic acid hybrids series 8, 9 and 10 possessing the essential structure requirements for anticonvulsant activity was synthesized starting from cycloalkanones. All final target compounds were primary screened for chemically and electrically induced seizures using pentylenetetrazole “scPTZ” and maximal electroshock seizure “MES” models. In phase I anticonvulsant evaluation compounds 8b and 10b exhibited the highest potency among all the target compounds with 100% protection towards chemically induced seizures. Results of phase II anticonvulsant screening showed that compounds 8b and 10b are more potent than standard drug ethosuximide by about 11 and 9 fold, respectively. Regarding MES test, compounds 8b and 9a-d exhibited 100% protection with ED50 values ranged between 0.107–0.177 mmol/Kg. All final compounds did not display any signs of motor impairment in the neurotoxicity screening test. Also, compounds 8a, 9a-d and 10b were devoid of hepatotoxicity as shown by measurement of serum levels of liver enzymes, albumin as well as total protein. Moreover, the cyclohexyl derivative 10b produced a significant increase of Gamma-aminobutyric acid “GABA” brain’s content of mice compared to control group confirmed its GABAergic modulating activity. Molecular docking, physicochemical and pharmacokinetic properties were carried out for all compounds as well. These outcomes support that cycloalkanecarboxamide parabanic acid hybrid is a promising scaffold to pave the way towards further development of novel class of antiepileptic drugs.

Synthesis, crystal structure and screening for anticonvulsant and antianxiety activities of three new Ni(II), Cu(II), and Zn(II) dithiocarbamate complexes

A potassium N-(4-fluorobenzyl) N-(naphthalen-1-ylmethyl) dithiocarbamate ligand (fbnm) has been isolated in a basic medium and its Ni(II), Cu(II), and Zn(II) complexes 1–3 were synthesized. All new compounds have been characterized by elemental analyses, magnetic susceptibility, IR, NMR, and UV–Vis techniques. Complexes 2 and 3 have been further characterized by single-crystal X-ray diffraction data. Zn(II) complex adopts tetrahedral geometry whereas Ni(II) and Cu(II) complexes adopt square planar geometry around the metal ions. In addition, the bite angles found around the metal chelate rings in complexes 2 and 3 suggest that these geometries are slightly distorted from regular geometry. Complexes 2 and 3 are stabilized by intermolecular CH···S, CH···π and CH···F interactions. The thermal degradations of metal complexes 1–3 have been examined by TG-DTA data which designates that metal sulfide is formed as the final entity. The anticonvulsant activity of ligand fbnm and its Ni(II), Cu(II), and Zn(II) complexes have been tested through MES test and PTZ induced convulsion test and found that complex 2 may be used as an anticonvulsant compound in the future by further biochemical or neurotransmitter estimations to control the onset of generalized tonic-clonic seizures. The antianxiety activity has also been performed via Elevated plus maze and Open field test and observed that all synthesized compounds are non-significant for anti-anxiety effect.

Synthesis and anticonvulsive activity of new 1,3-diazaadamantane derivatives

The work is devoted to the synthesis and study of the neurotropic activity of some derivatives of 3,7-diazabicyclo/3.3.1/nonanes. For this, various 5,7-dialkyl, methylphenyl, diphenyl 1,3-diazaa-damantanes 1 were synthesized, which, upon interaction with acid chlorides of aliphatic, aromatic and heterocyclic acids, were converted into the corresponding 3,7-diazabicyclo/3.3.1/nonanes. The anticonvulsant activity of the synthesized compounds was studied. Among them, substances with pronounced anticorazole activity were identified.

In-vivo Evaluation of Anticonvulsant activity of Juglans regia fruit extract

Epilepsy is a chronic disorder of the brain that affect people worldwide. Nearly about 50-80% of the patients with epilepsy are controlled with currently available antiepileptic drugs. But these drugs cannot able to control seizures effectively in about 10-20% of the patients. The treatment of epilepsy still remains inadequate even though new anticonvulsants are being developed. The present study was undertaken to investigate effect of J.regia in management of seizures.100 mg fruit extract was administered in seperate groups of animal. The J.regia fruit extract shows the anticonvulsant activity in animal model.

Comparative Analysis of Anticonvulsant Activity of Trans and Cis 5,5'-Diphenylhydantoin Schiff Bases.

Recently, the four 5,5'-diphenylhydantoin Schiff bases, possessing different aromatic species (SB1-Ph, SB2-Ph, SB3-Ph and SB4-Ph) were synthesized, characterized, and evaluated for anticonvulsant activity in combination with phenytoin. In the present study, the SB1-Ph and SB4-Ph compounds were selected, based on their anticonvulsant potency, and compared with their cis isomers, prepared after a one-hour exposure to the UV source, for their anticonvulsant potency in the maximal electroshock (MES) test and the kainate (KA)-induced status epilepticus (SE) test in mice. In the MES test, the cisSB1-Ph compound exhibited superior to phenytoin and trans isomer activity in the three tested doses, while the cisSB4-Ph compound entirely suppressed the electroshock-induced seizure spread at the highest dose of 40 mg/kg. Pretreatment with the cisSB1-Ph compound and the cisSB4-Ph at the doses of 40 mg/kg, respectively, for seven days, significantly attenuated the severity of KA SE compared to the matched control group pretreated with a vehicle, while phenytoin was ineffective in this test. The cisSB4-Ph but not the cisSB1-Ph demonstrated an antioxidant effect against the KA-induced SE in the hippocampus. Our results suggest that trans-cis conversion of 5,5'-diphenylhydantoin Schiff bases has potential against seizure spread in the MES test and mitigated the KA-induced SE. The antioxidant potency of cisSB4-Ph might be associated with its efficacy in mitigating the SE.

Pharmacognostic Evaluation of the Leaves of Thurnbegia laevis Nees (Acanthaceae)

Thurnbegia laevis Nees. belong to the Acanthaceae family. It is used in folklore medicine for the management of diabetes, piles, joint pains as well as skin related problems. This study aims to evaluate the leaves of the plant by employing the quality control parameters. The leaves of T. laevis were collected, identified, air-dried, pulverized and stored in glass bottles. Standard procedures were used to carry out microscopy on the fresh leaves, micromeritics, chemomicroscopy, fluorescence analysis, soluble-extractive values, moisture contents and ash values using powdered samples of the leaf. Methanol extract of the leaf was used to conduct GC-MS analysis. The result showed that the leaf was amphistomatic with diacytic stomata on both surfaces. The micromeritic studies showed that the leaf had an angle of repose of 37.47ᵒ, Carr’s Index of 23.01% and Hausner’s ratio of 1.3. Water-soluble, ethanol-soluble and methanol-soluble extractive values were 21%w/w, 10%w/w and 11%w/w, respectively. Fluorescence analysis of the leaf showed different colours indicating the presence of different phytochemicals. The moisture content, total ash, acid-insoluble and water-soluble ash values were 5.31%w/w, 15.18%w/w, 2.7%w/w and 5.6%w/w, respectively. Chemomicroscopy of the leaf powder showed the presence of mucilage, lignin, starch, cellulose and protein while, oil and calcium oxalate crystals were absent. The GC-MS analysis showed the presence of thirty-five (35) phytochemicals with compounds like n-Hexadecanoic acid, 9,12,15-Octadecatrienoic acid, Vitamin E, Stigmasterol, Supraene and, Benzoic acid. These compounds have antioxidant, anticonvulsant, antiserum, antifungal, hypoglycaemic, antimicrobial, anti-inflammatory and larvicidal activities. The results stated could be used to establish standards for the authentication of the fresh and powdered drug leaf products of Thunbergia laevis.

Gut-Brain-axis: effect of basil oil on the gut microbiota and its contribution to the anticonvulsant properties

BackgroundEpilepsy is a chronic neurological condition that disrupts the normal functioning of the brain and it is characterized by seizures. Research suggests the involvement of the Gut-Brain axis in epilepsy. This study seeks to determine the role of the gut microbiota in the anticonvulsant effect of basil oil (BO) using antibiotic-depleted and altered germ-free mice against naïve mice in Pentylenetetrazole (PTZ) induced seizure model. There is an ever growing interest in improvement of treatment outcomes in epilepsy and also in the development of newer therapeutic options, especially in the population of patients that do not attain seizure relief from available antiseizure medications (ASMs). According to research, gut microbiota can alter brain function and development. Increasing evidence suggests disrupting the delicate symbiotic balance existing between the gut and brain results in disease conditions. Also, the oil from Ocimum basilicum L., (BO) has been proven scientifically to significantly block clonic seizures induced by PTZ and picrotoxin in seizure models.MethodsThe microbiota of mice were depleted or altered by administering cocktail antibiotics and individual antibiotics respectively. DNA was isolated from mouse stool, and then the 16S ribosomal ribonucleic acid (16S rRNA) gene was quantitatively amplified using reverse transcription-polymerase chain reaction (RT-PCR). Amplicons were sequenced to determine the phylogenetic make-up of the bacteria involved. Metabolic profiles of the serum and stool of mice were determined using Proton (1H) Nuclear Magnetic Resonance (NMR) spectroscopy.ResultsCocktail antibiotic pre-treatment significantly reversed the anticonvulsant effect of BO by increasing frequency and duration of seizures but did not affect latency to seizure. In mice pre-treated with single antibiotics, the anticonvulsant effect of BO was lost as latency to seizures, frequency and duration of seizures increased compared to mice that received only BO. Assessment of the phylogenetic make-up of the microbiota in antibiotic pre-treated mice showed a distorted composition of the microbiota compared to the control group.ConclusionDepletion of the microbiota significantly reversed the anticonvulsant actions of BO. The concentrations of short chain fatty acids (SCFAs) was higher in stool than in the serum of the mice. Administration of BO probably does not influence the microbial composition within the mouse microbiota. The elevated ratio of Firmicutes to Bacteroidetes in microbiota-depleted groups might have contributed to the reversal of anticonvulsant actions of BO.

A Combined Ligand- and Structure-Based Virtual Screening To Identify Novel NaV1.2 Blockers: In Vitro Patch Clamp Validation and In Vivo Anticonvulsant Activity.

Epilepsy is a neurological disorder characterized by recurrent seizures that arise from abnormal electrical activity in the brain. Voltage-gated sodium channels (NaVs), responsible for the initiation and propagation of action potentials in neurons, play a critical role in the pathogenesis of epilepsy. This study sought to discover potential anticonvulsant compounds that interact with NaVs, specifically, the brain subtype hNaV1.2. A ligand-based QSAR model and a docking model were constructed, validated, and applied in a parallel virtual screening over the DrugBank database. Montelukast, Novobiocin, and Cinnarizine were selected for in vitro testing, using the patch-clamp technique, and all of them proved to inhibit hNaV1.2 channels heterologously expressed in HEK293 cells. Two hits were evaluated in the GASH/Sal model of audiogenic seizures and demonstrated promising activity, reducing the severity of sound-induced seizures at the doses tested. The combination of ligand- and structure-based models presents a valuable approach for identifying potential NaV inhibitors. These findings may provide a basis for further research into the development of new antiseizure drugs for the treatment of epilepsy.

Pharmacological Activity and Mechanisms of Action of Terpenoids from Laurus nobilis L.

Abstract: Native to the Southern Mediterranean region, Laurus nobilis L. (Family Lauraceae) is an evergreen shrub or tree found in warm climate regions with high rainfall. The leaves and essential oil of this plant have been widely used as condiments, spices, and flavoring agents in the culinary and food industries. The whole plant is also used for the traditional treatment of various diseases, including cough, asthma, hemorrhoids, rheumatic pain, diarrhea, intestinal, and cardiac diseases. Previous phytochemical investigation of this plant demonstrated the presence of a variety of secondary metabolites, especially terpenoids. The present study aims to critically analyze comprehensive literature on the pharmacological activity and mechanisms of action of terpenoids from Laurus nobilis L. The available information on the pharmacological activity of terpenoids from L. nobilis L. was obtained from textbooks, theses, as well as published articles through a variety of libraries and electronic databases. The present study demonstrated that L. nobilis is rich in terpenoids, with more than 200 entities identified in reported studies. Terpenoids from L. nobilis have shown a wide range of pharmacological activities, including anti-inflammatory, antidiabetic, antifungal, antibacterial, immunomodulatory, anticonvulsant, antioxidant and cytotoxic activities. The mechanisms of action of most of these terpenoids included the imbalance of the ionic permeability of the cell membrane (anti- inflammatory and antimicrobial activities), modulation of the effects of gamma-aminobutyric acid (GABA) nergic neurotransmission (anticonvulsant activity), and the inhibition of inflammatory responses, prevention of metastasis, and induction of apoptosis (cytotoxic effect), among others. Referring to in vitro studies, terpenoids of L. nobilis L. have shown a variety of biological activities. However, more cytotoxic and in vivo studies and detailed mechanisms of action of the bioactive terpenoids are recommended.

Study of the anticonvulsant activity of the original valproic acid amino ester in various models of convulsive syndrome

Introduction. Despite a significant number of antidotes (atropine, pyridoxine) and anti-seizure drugs in clinical practice (benzodiazepines, barbiturates, valproates, anesthetics), the development of new antidotes for the relief of refractory seizures and recurrence of convulsive syndrome is actual problem. 
 The aim of the work was to study the specific pharmacological activity of a new original derivative of valproic acid in an experiment on models of convulsive syndrome with different mechanisms of action.
 Material and methods. A comparative study of the effectiveness of the original substance ((1-methylpiperidin-4-yl)-2-propylpentanoate hydrochloride, VAA) was carried out on electroshock, GABA-lytic, catecholamine-dependent seizure models in rats and mice.
 Results. A significant decrease in seizure activity was revealed in the group with prophylactic administration 
 of VAA in the dose range of 11, 27 and 65 mg/kg in comparison with the control group received only phenylcarbamate. In an intergroup comparison, a low dose (11 mg/kg) more than others had an effect on the latent period of the onset of phenylcarbamate seizures, an average dose (27 mg/kg) reduced the duration of the seizure period, a high dose (65 mg/kg) affected the severity of convulsions, while the integral indicator (convulsive activity) did not differ between the medium and high dose subgroups. There was no significant decrease in seizure activity in models with the use of corazol, camphor, and the model of maximum electric shock.
 Limitations. Testing of new pharmaceutical substances (study of efficacy and safety) should be carried out on laboratory animals before confirmation of efficacy in humans. The quantity of animals was limited by the need to comply with bioethical principles and sufficient number for statistically significant results and amounted 
 6 individuals in each group.
 Conclusion. The release of valproic acid during the metabolism of VAA is slow and its concentration is insufficient to realize the universal anticonvulsant activity of VAA. It is necessary to further study the effect on cognitive functions and neuroprotective properties. Since antidote efficacy superior to atropine has been previously demonstrated, VAA is recommended for development as an antidote for organophosphorus poisoning.

Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5'-Diphenylhydantoin Schiff Bases and Phenytoin.

Four 5,5'-diphenylhydantoin Schiff bases possessing different aromatic species (SB1-SB4) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives SB1-Ph, SB2-Ph, SB3-Ph, and SB4-Ph, containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The SB2-Ph exhibited the highest potency to suppress the seizure spread with ED50 = 8.29 mg/kg, comparable to phenytoin (ED50 = 5.96 mg/kg). While SB2-Ph did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED50 by more than 2× and raised the protective index by more than 7× (phenytoin+SB2-Ph). The strongest correlation between in-vivo and docking study results was found for ligands' interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.

Mechanochemical synthesis and anticonvulsant activity of 3-aminopyrrolidine-2,5-dione derivatives

A series of 3-aminopyrrolidine-2,5-dione derivatives was synthesized and tested for anticonvulsant activity. Succinimide derivatives were obtained from a simple solvent-based reaction and a mechanochemical aza-Michael reaction of maleimide or its N-substituted derivatives with selected amines. The structure of the compounds was confirmed by spectroscopic methods (NMR, FT-IR, HPLC, ESI-MS, EA and XRD for four compounds). The cytotoxic activity of the succinimide derivatives was evaluated using HepG2 cells for hepatocytotoxicity and SH-SY5Y cells for neurocytotoxicity. None of the studied compounds showed hepatocytotoxicity and two showed neurocytotoxicity. Initial anticonvulsant screening was performed in mice using the psychomotor seizure test (6 Hz, 32 mA). The selected compounds were evaluated in the following acute models of epilepsy: the maximal electroshock test, psychomotor seizure test (6 Hz, 44 mA), subcutaneous pentylenetetrazole seizure test, and acute neurotoxicity (rotarod test). The most active compound 3-((4-chlorophenyl)amino)pyrrolidine-2,5-dione revealed antiseizure activity in all seizure models (including pharmacoresistant seizures) and showed better median effective doses (ED50) and protective index values than the reference compound, ethosuximide. Furthermore, 3-(benzylamino)pyrrolidine-2,5-dione and 3-(phenylamino)pyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz and MES tests, and 3-(butylamino)−1-phenylpyrrolidine-2,5-dione and 3-(benzylamino)−1-phenylpyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz test. All active compounds demonstrated low in vivo neurotoxicity in the rotarod test and yielded favourable protective indices.