New dibenzofuranone-oxime derivatives were designed based on active structures of oxime esters. Compounds of the proposed group were synthesized using 3,4,6,7,8,9-hexahydrodibenzo[ b,d ]furan-1(2 H )-one oxime and aromatic acid chlorides. The anticonvulsant activity of the new compounds was studied. The structure— activity relationship was analyzed. Compound 1a [3,4,6,7,8,9-hexahydrodibenzo[ b,d ]furan-1(2 H )-one O -(3,4-dichlorobenzoyl)oxime] was the most active compound after i.p. injection to mice in the maximal electroshock test over a wide dose range of 20 – 100 mg/kg. Compound 1a at doses of 10 and 30 mg/kg exhibited antihypoxic activity in a hypoxia test with hypercapnia in a hermetic chamber and anti-ischemic activity at a dose of 10 mg/kg in a rat ischemic stroke model.

The aim was to study the effect of lacosamide on epileptiform activity (EрA) and structure-function relations in the brain in the course of development of the epileptic system in rats with cobalt-induced chronic epilepsy. Materials and methods. To model chronic focal epilepsy, we used topical applications of cobalt on the sensorimotor zone of the rat cortex. The effect of lacosamide (20 mg/kg) on the cobalt-induced epileptiform activity was analyzed in parallel with with the monitoring of spectral-coherent changes in the brain during the development of the epileptic system (ES). Results. In the first 30 minutes after the administration, lacosamide briefly enhanced the EрA in the hippocampus and ipsilateral cortex, and also strengthened the cortical-hippocampal (at stage 1) and cortical-hypothalamic connections (at stage 2). Two hours after the drug administration, a decrease in EрA was observed at stages 1 and 2 of the ES development, especially in the contralateral cortex and hippocampus. At all frequency ranges, the level of the inter-center connections decreased (most pronounced in the cortical-hippocampal links). Conclusion. The effect of lacosamide on EрA in the rat brain with cobalt-induced epileptogenic focus is characterized by a decrease in EрA, two hours after the drug administration. This effect is most expressed in the cortex and hippocampus, and is accompanied by a decrease in the level of the corticalhippocampal connections.

The novel group of 4-GABA-3-nitrocoumarines, 1-thiocoumarines, quinolone-2-ones, and their derivatives was designed as potential anticonvulsants using GABA pharmacophore and corresponding heterocyclic moieties. A number of compounds of this group were synthesized and studied in the maximum electroshock seizure (MES) test and in the model of primary-generalized convulsions caused by subcutaneous pentylenetetrazole (scPTZ) in mice. The most active compound in the MES test was found to be 1a (N-(3-nitrocoumarin-4-yl)-4-aminobutyric acid) at a dose range of 60–80 mg/kg that increased the number of survived animals up to 60% in comparison with the control group, whose survival rate was 10%. Compounds 1d (N-(3,6-dinitrocoumarin-4-yl)-4-amino-butyric acid methyl ester) at doses of 10–40 mg/kg and 3a (N-(3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)-4-amino-butyric acid methyl ester) at a dose of 12.5 mg/kg had the most pronounced anticonvulsant effect in scPTZ test.

Novel thiocoumarins and quinolin-2-ones were synthesized and screened for anticonvulsant activity. The structure–activity relationship of a series of synthesized compounds and previously prepared coumarin derivatives was analyzed. The methyl ester of N -(3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)-4-aminobutyric acid ( 3a ) at a dose of 12.5 mg/kg (i.p.) had the greatest anticonvulsant activity in mouse tests.

The synthesis and anticonvulsant activity of new coumarin derivatives are reported. N -(3-Nitrocoumarin-4-yl)-4-aminobutyric acid ( 1a ) at doses of 60 and 80 mg/kg (in the MES test) and methyl N -(3,6-dinitrocoumarin-4-yl)-4-aminobutyrate ( 1e ) at doses of 20 and 40 mg/kg (in the corazole antagonism test) possessed the greatest anticonvulsant activity of the synthesized compounds. The results indicated that the coumarin derivatives were promising for further development as potential anticonvulsant agents.

The aimis to develop an antiepileptic drug based on polymer nanoparticles with 2-ethyl-6-methyl-3-oxypyridine succinate to facilitate the drug transport through the blood-brain barrier.Materials and methods.The nano-drug was created using the biologically active substance 2-ethyl-6-methyl-3-hydroxypyridine succinate and polybutyl cyanoacrylate (PBCA) nanoparticles. The advantages of this nano-form over the active ingredient of the same drug were studied using experimental models: the maximum electroshock test (MES), the antagonism test with corazol, models with a cobaltinduced epileptic focus and secondary generalized convulsions, and models of status epilepticus.Results.The antiseizure effects of the nanoform on the experimental models of epilepsy are identified.Conclusion.The nano-drug reduces the number of secondary generalized clonic-tonic seizures by 7.8 times; it also reduces 10-fold the animal mortality and diminishes the seizure manifestations that occur in the interictal period of the epileptic status.

New 4-phenylpyrrolidone derivatives were designed from racetam structures that combine nootropic and anticonvulsant activity. The proposed compounds were synthesized using 4-phenylpyrrolidone and aromatic amines. The anticonvulsant activity of the new compounds was studied. The structure–activity relationship was analyzed. The most active compound was the 2,6-dimethylanilide of (2-oxo-4-phenylpyrrolidin-1-yl)acetic acid at doses of 2.5 – 5.0 mg/kg, which surpassed the reference drug levetiracetam at doses of 2.5 – 600 mg/kg in all tests and possessed distinct nootropic activity that was comparable to that of the reference nootropic drug piracetam at a dose of 400 mg/kg.

We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant action. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholinoethyloxime oxalate (1a), i.p. doses of 60 – 150 mg/kg of which increased the survival of mice to 100%. The best effect in the corasol antagonism test was obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c), i.p. doses of 12.5 mg/kg of which increased the survival of mice to 67% and the latent period of onset of generalized tonic-clonic convulsions to 52 sec. Compound 1a had low toxicity (the i.p. LD50 in mice was 316 mg/kg) and a therapeutic index of 21.

The aim of this study was to evaluate the anti-seizure effect of Levetinol tablet (Geropharm) on the cobalt-induced chronic epilepsy.Materials and methods. A model of cobalt-induced epilepsy was created by applying cobalt powder to the sensorimotor zone of the rat cortex. The effects of Levetinol were studied at the early stage of the epileptic system (ES) formation (on day 2 after the cobalt application), and then at the stage of fully developed ES (on day 6 after the cobalt application).Results. The present study showed that at the early stage of ES development, Levetinol at doses of 50 and 200 mg/kg had no statistically significant effect on the development of paroxysmal activity in both primary and secondary epileptic foci: in the ipsi- and contralateral cortex, hypothalamus and hippocampus. On day 6 of the cobalt-induced epilepsy, a significant suppression of paroxysmal activity in the above structures of the brain was observed with the administration of Levetinol at a dose of 200 mg/kg. The most pronounced anti-seizure effect was found in the hippocampus; that was expressed in normalization of the bioelectrical activity and appearance of the regular theta rhythm.Conclusion. The effects of Levetinol are largely manifested in the hippocampal foci of epileptiform activity and, to a lesser extent, in the cortical foci.

Isatin (indole-2,3-dione) is an endogenous indole found in the mammalian brain, peripheral organs and body fluids. It acts as a neuroprotector, which decreases manifestation of locomotor impairments in animal models of Parkinson’s disease. A wide range of biological activity of isatin is associated with interaction of this regulator with numerous isatin-binding proteins. The aim of this study was to investigate the profile of brain isatin-binding proteins in mice with MPTP-induced Parkinsonism characterized by maximal manifestation of locomotor impairments (90 min) and seven days after administration of this neurotoxin. A single dose administration of MPTP (30 mg/kg, ip.) was accompanied by locomotor impairments in the open field test 90 min after administration; seven days after MPTP administration locomotor activity of mice significantly improved but did not reach the control level. Five independent experiments on proteomic profiling of isatin-binding proteins resulted in confident identification of 96 ± 12 proteins. Development of MPTPinduced locomotor impairments was accompanied by a significant decrease in the number of isatin-binding proteins (63 ± 6; n = 5; p < 0.01). Seven days after MPTP administration the total number of identified proteins increased and reached the control level (132 ± 34; n = 4). The profiles of isatin-binding proteins were rather specific for each group of mice: in the control group these proteins (which were not found in both groups of MPTP-treated mice) represented more than 70% of total proteins. In the case of MPTP treated mice this parameter was 60% (90 min after MPTP administration) and >82% (seven days after MPTP administration). The major changes were found in the groups of isatin-binding proteins involved into cytoskeleton formation and exocytosis, regulation of gene expression, cell division and differentiation and also proteins involved in signal transduction.

Objective of the research is to evaluate the anticonvulsant effect of the new original compound GIZH-298 (4-benzoylpyridine oxime derivative) versus valproic acid (VPA) in a model of epilepsy in rats with cobalt-induced lesions.Materials and methods. Modeling of epileptic status was performed using the technique of creating a chronic epileptogenic focus caused by the application of cobalt to the sensorimotor zone of the rat cortex, followed by intraperitoneal administration of homolecysteine thiolactone. Compounds GIZH-298 and VPA were introduced against the background of development of electrographic status with behavioral convulsive seizure manifestations.Results. The study revealed that GIZH-298 at a dose of 60 mg/kg (i. p.) in 50 minutes after injection reduces the number of high-amplitude generalized discharges caused by homocysteine thiolactone in the ipsilateral and contralateral cortex (46-fold decrease), in the hippocampus and hypothalamus (28-fold decrease); eliminates (in 100% of the animals) the generalized tonic-clonic seizures that arise in the advanced stage of status epilepticus. VPA at a dose of 100 mg/kg (i. p.) in 3 hours after injection significantly suppresses the EpA in all evaluated structures with the maximum value in the hypothalamus (28-fold decrease), and after 5 hours in the ipsilateral and contralateral (33-fold decrease). At the same time, VPA eliminates generalized motility of status epilepticus only in 71% of the animals and protects from death 86% of the rats.Conclusion. The compound GIZH-298 significantly earlier (for 2 hours) than the VPA (100 mg/kg) and at a lower dose (60 mg/kg) fully eliminates electrographic (in all evaluated brain structures with the greatest efficiency in the contralateral cortex and the hypothalamus) and behavioral manifestations of unfolded status epilepticus and prevents deaths in 100%.

Mitochondria play an important role in molecular mechanisms of neuroplasticity, adaptive changes of the brain that occur in the structure and function of its cells in response to altered physiological conditions or development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson's disease in various experimental animal models, and also neuroprotectors. Good evidence exists in the literature that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria), and neuroprotective effects of certain antiparkinsonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS. The 19S proteasomal Rpn10 subunit is considered as a ubiquitin receptor responsible for delivery of ubiquitinated proteins to the proteasome proteolytic machinery. In this study, we investigated proteomic profiles of mouse brain mitochondrial Rpn10-binding proteins, brain monoamine oxidase B (MAO B) activity, and their changes induced by a single-dose administration of the neurotoxin MPTP and the neuroprotector isatin. Administration of isatin to mice prevented MPTP-induced inactivation of MAO B and influenced the profile of brain mitochondrial Rpn10-binding proteins, in which two pools of proteins were clearly recognized. The constitutive pool was insensitive to neurotoxic/neuroprotective treatments, while the variable pool was specifically influenced by MPTP and the neuroprotector isatin. Taking into consideration that the neuroprotective dose of isatin used in this study can result in brain isatin concentrations that are proapoptotic for cells in vitro, the altered repertoire of mitochondrial Rpn10-binding proteins may thus represent a part of a switch mechanism from targeted elimination of individual (damaged) proteins to more efficient ("global") elimination of damaged organelles and whole damaged cells.

The purpose of this research was to study electric and physiological mechanisms of the achievement of the antoconvulsant effect of the new original beprodon combination together with determination of determinant brain structures – therapeutic targets.Materials and Methods. Partial (focal) and secondary generalized convulsions were generated using the method of creation of a chronic epileptogenic focus, caused by the cobalt application on rats’ brain.Results: it was revealed, that at the first stage of the epileptic system (ES) beprodone is targeted to cortical focuses, and at the second stage – to subcortical focuses, generating epileptic activities. Conclusion: the beprodone effect depends on the stage of the epileptic system development and is targeted to determinant focuses.

The article considers the peculiarities of the spatial organization of brain potentials in epileptic patients with a lesion in the right hemisphere. We identified violations of the spatial organization of brain potentials, which allow you to objectify violations of structural-functional relationships in epileptic patients with a lesion in the right hemisphere with the formation of multilevel pathological neural networks involving intact neural populations. Specific changes of hemispheric interactions characterized by a significant decrease in average levels of coherence in the occipital, parietal and anterio temporal areas in most frequency bands. The obtained data allow to suppose the specificity of the changes in alpha activity, characterized by the reciprocity of changes in the alpha rhythm in the range of 9-10 and 11-12 number`s.

This article reviews the issues of experimental and clinical epileptology. For the development and implementation of new medications and technologies of medicinal interventions, as well as investigation of main “targets” for anti-epileptic drugs, it is necessary to develop the experimental models of various forms of epilepsy and epileptic seizures. To this end, we studied the alterations of cerebral electrical activity in rats with chronic cobalt epileptogenic focus which represents an optimal experimental model of epileptic state. The significance of hypothalamus was shown to be the lead (determinate) structure within the pathologic epileptic system during formation of secondary generalized seizures. The drug” targets” and possibilities for combined administration of anticonvulsants and antioxidants have been revealed. Pharmaco-genetic investigations enable us to predict the effects of different antiepileptic drugs.

Possibilities of application the prolonged form valproic acid and antioxidant in secondary - generalized seizures was investigated in experiment and in clinical study in patients with epilepsy. In rats with cobalt-induced epilepsy their efficacy has been revealed by the suppression of determinant hearth in the cortex, which is as a hypothalamus the leading focus for the developing epileptic system in forming of secondary - generalized seizers. Depakine Chronosphere statistically significantly surpasses Depakine Chrono in activity of removal epileptiform discharges in electrocorticogrammes it was determined optimal daily dose of antioxidant Mexidol and interval between the taking of Depakine Chronosphere and injection of antioxidant. Combination of antioxidant and anticonvulsant promotes greater control of seizures in patients with focal symptomatic and/or cryptogenic epilepsy.

The aim of this study was to investigate the electrophysiological and neurochemical mechanisms of the anticonvulsant effect of a new original compound GIZH-298 and to define the leading structure as the target for influence compound. Materials and Methods. The partial (focal) and secondary generalized seizures were modeled by methods of creation a chronic epileptic focus that was caused by cobalt applique on the brain of rats. The liquid chromatography (HPLC) analysis used for neurochemical study of the effect GIZH-298. There was studied the effect on metabolism and quantity of biogenic amines in the brain structures of rats. Results. It was found that GIZH-298 at a dose of 60 mg / kg (i.p.) has a pronounced effect on the primary and especially secondary generalized epileptic foci in various brain structures with a primary influence on the cortex. GIZH-298 at a dose of 60 mg / kg caused a statistically significant increase in the content of serotonin and dopamine in the frontal cortex after 30 minutes after the administration and reduced the rate of metabolism of dopamine in the dorsal striatum. Conclusion. The anticonvulsant effect GIZH-298 is enhanced with increased of epileptic system, may be due to increased synthesis of serotonin and dopamine in the cortex, and decreased metabolism of the latter in the striatum.

We studied changes in the levels of inhibitory and excitatory neurotransmitters in female rat brain structures during different phases of the estrous cycle in health and after creation of a cobalt epileptogenic focus at stage I of epileptogenic system development. The most pronounced shifts were found in the contralateral cortex, where the levels of GABA and glycine decreased significantly during the diestrus-2 phase (corresponding to menstruation), which attests to a convulsive threshold decrease during this period.

He aim of the study was to investigate the influence of a derivative of 4-benzoyl pyridine connection, GIZ-298 on electroencephalographic manifestations ranvulsive activity in the brain structures of rats with cobalt-induced focal epilepsy in the first stage of the formation of epileptic system. Methodology of the study. We used the technique of creation (by an application of cobalt to the brain of rats) chronic epileptogenic focus, generating paroxysmal activity in different brain structures: the ipsi- and contralateral cortex, hippocampus and hypothalamus. The results of the study. Established that injection ofGIZ-298 at a dose of 60 mg/kg (intraperitoneally, once) on the first stage of development of the system eliminates epileptic EEG manifestations of seizure activity in all the investigated structures of the brain, with the greatest efficiency in the ipsilateral cortex and the hypothalamus, significantly reducing both the number and duration of seizure discharges.