Animal models of epilepsy are of great importance in epileptology. They are used to study the mechanisms of epileptogenesis, and search for new genes and regulatory pathways involved in the development of epilepsy as well as screening new antiepileptic drugs. Today, many methods of modeling epilepsy in animals are used, including electroconvulsive, pharmacological in intact animals, and genetic, with the predisposition for spontaneous or refractory epileptic seizures. Due to the simplicity of manipulation and universality, genetic models of audiogenic epilepsy in rodents stand out among this diversity. We tried to combine data on the genetics of audiogenic epilepsy in rodents, the relevance of various models of audiogenic epilepsy to certain epileptic syndromes in humans, and the advantages of using of rodent strains predisposed to audiogenic epilepsy in current epileptology.

The review presents the results of studies concerning the multimodal mechanism of action of the Russian original drug Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which provides its neuroprotective effect and a wide range of clinical effects. The Mexidol molecule is represented by two related and functionally significant components: 2-ethyl-6-methyl-3-hydroxypyridine and succinate. The presence of 3-hydroxypyridine in the structure of Mexidol is associated with the antioxidant and membranotropic activity of the drug, the ability to reduce glutamate excitotoxicity, and modulate the work of receptors and ion channels. The succinate in Mexidol provides the ability to induce the succinate receptor SUCNR1, improve succinate signaling, stimulate mitochondriogenesis, restore mitochondrial respiration and activate the Krebs cycle, increase the energy status of the cell, which causes the antihypoxic effect of the drug. Mexidol enhances the expression of transcription factors HIF-1α, Nrf2 under hypoxic conditions, has neuroregenerative activity mediated by increased levels of the main regulatory molecules — neurotrophic factors NGF, IGF1, BDNF and VEGF in areas of ischemic brain damage, and also has a positive effect on PGC-1a, which coordinates aerobic metabolism and energy stability of cells. These features distinguish Mexidol from other succinic acid preparations.

Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABA_A receptor’s benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABA_A receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABA_ARs-dependent pharmacological effects.

Brain-derived neurotrophic factor (BDNF) is a classic neuroprotective and pro-regenerative factor in peripheral and central nervous tissue. Its ability to stimulate the restoration of damaged nerve and brain tissue after ischemic stroke and intraventricular hemorrhage has been demonstrated. However, the current concept of regeneration allows us to assert that one factor, even if essential, cannot be the sole contributor to this complex biological process. We have previously shown that urokinase-type plasminogen activator (uPA) complements BDNF activity and stimulates restoration of nervous tissue. Using a model of intracerebral hemorrhage in rats, we investigated the neurotrophic and neuroprotective effect of BDNF combined with uPA. The local simultaneous administration of BDNF and uPA provided effective neuroprotection of brain tissue after intracerebral hemorrhage, promoted survival of experimental animals and their neurological recovery, and decreased lesion volume. The study of cellular mechanisms of the observed neurotrophic effect of BDNF and uPA combination revealed both known mechanisms (neuronal survival and neurite growth) and new ones (microglial activation) that had not been shown for BDNF and uPA. Our findings support the concept of using combinations of biological factors with diverse but complementary mechanisms of action as a promising regenerative approach.

We studied behavioral and neurochemical alterations that were induced by modeling of Alzheimer’s disease (AD) using bilateral intracerebroventricular administration of Aβ25–35at a dose of 7.5 nmol...

На мышах и крысах изучено влияние 5 оригинальных производных 4-фенилпирролидона в тестах оценки противосудорожной и мнемотропной активности в сравнении с леветирацетамом и пирацетамом. В тестах максимального электрошока и антагонизма с коразолом соединение ГИЖ-290 ослабляло судороги и повышало выживаемость мышей, тогда как леветирацетам лишь увеличивал латентное время наступления клонического приступа в тесте антагонизма с коразолом. Противосудорожная активность ГИЖ-290 и леветирацетама отмечена в тесте литий-пилокарпиновых судорог на крысах, когда оба вещества увеличивали выживаемость животных, а также продолжительность латентного периода начала генерализованного приступа. ГИЖ-290 и пирацетам уменьшали время обнаружения платформы в водном лабиринте Морриса, тогда как леветирацетам был неэффективен в начальной стадии обучения. Все вещества способствовали облегчению воспроизведения навыка через 5 сут после обучения, увеличивая время пребывания мышей в секторе с платформой. Таким образом, соединение ГИЖ-290 характеризуется сочетанием противосудорожной и мнемотропной активности, существенно превосходя леветирацетам и пирацетам по уровню эффективных доз.