Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.

Electromagnetic radiation at the mobile connection frequency (1 GHz) at maximum energy flow density (10 microW/cm(2)) permitted in Russia causes serious functional disorders in the studied unicellular hydrobionts infusoria Spirostomum ambiguum: reduction of their spontaneous motor activity. The form of biological reaction is uncommon: the effect is threshold, overall, and does not depend on the duration of microwave exposure.

Current antiepileptic strategies aim to normalize the interaction of the excitatory and inhibitory systems, which is ineffective in treating patients with drug-resistant epilepsy. Neuroinflammatory processes in the epileptic focus and its perifocal area can trigger apoptosis and also contribute to the development of drug resistance. The level of pro- and anti-apoptotic proteins (p-NF-kB, TNF-α, p53, FAS, caspase-3, caspase-9) was analyzed in intraoperative biopsies of the temporal lobe gray and white matter in the brain of patients with drug-resistant epilepsy. An increased level of pro-apoptotic proteins was revealed in the cortex and perifocal area’s white matter against the background of an imbalance of protective anti-apoptotic proteins. It appears that the activation of the extrinsic pathway of apoptosis occurs in the perifocal area, while in the epileptic focus, there are proteins responsible for the activation of the anti-apoptotic survival pathways. Active neuroinflammation in the epileptic focus and perifocal area of the temporal lobe may contribute to the development of the resistance to antiepileptic drugs and the progression of neurodegeneration in such patients.

Neuroglial apoptosis and neuroinflammation play an important role in epileptogenesis. The aim of this study is to evaluate neuronal and glial apoptosis in association with neuroinflammation in brain epileptic focus and inflammatory changes in blood in patients with focal drug-resistant epilepsy (DRE). Pathological changes in the temporal lobe in epilepsy (histology, transmission electron microscopy), levels of apoptotic and neuroinflammatory proteins: active caspase-3 (immunohistochemistry), full-length form caspase-3, caspase-9, FAS, FAS-L, NF-kB, TNF-α, p53 (Western blot), and cytokine levels in blood: IL-1β, IL-2, IL-4, IL-7, TNF-α, etc. (multiplex analysis) were studied. In the present work, ultrastructural and immunohistochemical apoptotic signs were found in neurons and oligodendrocytes in the temporal lobe of DRE patients. Levels of proinflammatory cytokines that play a role in apoptosis (TNF-α, FAS, NF-kB) were increased. The blood concentration of IL-4, IL-7, TNF-α is increased and IL-2 is reduced. Oligodendroglial apoptosis has been shown to play an important role in DRE pathogenesis and to explain demyelination. Thus, a comprehensive analysis of revealed changes in the blood and brain in DRE patients showed the neuroinflammation in the epileptic focus, which was combined with the development of apoptosis of glial cells and neurons. This creates conditions for the development of drug resistance and the epilepsy progression.

Aim. To study markers of blood-brain barrier dysfunction (BBB) in patients with pharmacoresistant epilepsy (PhRE) – the amount of VEGF in endotheliocytes of brain capillaries, TNF-α in brain tissue and cytokine profile in blood serum.Materials and methods. The study included 30 patients with PhRE who underwent anterior temporal bloc resection. Histological samples of the brain were examined to assess the amount of VEGF and TNF-α; the concentration of cytokines in the blood serum was determined.Results. In the PhRE group, the densitometric density of cells expressing VEGF and the amount of TNF-α in the epileptogenic focus were higher than in the control groups (p < 0.001; p < 0.05). Compared with the control, the serum concentrations of IL-2 (0.98 ± 0.28 pg/ml vs. 2.80 ± 0.71 pg/ml; p < 0.001), IL-8 (14.04 ± 1.46 pg/ml vs. 26.13 ± 3.80 pg/ml; p < 0.001) and EGF (43.72 ± 5.63 pg/ml vs. 83.62 ± 24.06 pg/ml; p < 0.05) were statistically significantly lower in the PhRE group, and the amount of TNF-α (33.09 ± 1.23 pg/ml vs. 24.85 ± 1.32 pg/ml, p < 0.05), IL-4 (43.73 ± 2.57 pg/ml vs. 32.37 ± 5.80 pg/ml, p < 0.05), IL-5 (43.73 ± 2.57 pg/ml vs. 32.37 ± 5.80 pg/ml; p < 0.05), IL-7 (16.65 ± 3.07 pg/ml vs. 8.13 ± 1.67 pg/ml; p < 0.05), GRO (growth-regulated protein) (3054.0 ± 200.8 pg/ml vs. 1367.0 ± 187.3 pg/ml; p < 0.001), VEGF (316.10 ± 55.28 pg/ml vs. 95.22 ± 15.78 pg/ml; p < 0.01) are statistically significantly higher. There were no significant differences in the concentration of IL-1β, IL-1RA, IL-10 and IFN-γ between the PhRE group and the control.Conclusion. Based on the studied cytokine profile, there is no systemic inflammation in patients with PhRE. The established overexpression of VEGF in the brain and an increase in its concentration in the blood, combined with a decrease in serum EGF concentrations and an increase in GRO, as well as pro-inflammatory factors, indicates damage to the BBB. A high amount of TNF-α in the epileptic focus indicates neuroinflammation, and an increased concentration of this marker can be found in the blood of patients with BBB dysfunction.

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Изучение глионейронального апоптоза и нейровоспаления крайне важно для понимания причин развития эпилепсии. В настоящее время основное внимание уделяется нейрональному апоптозу и отдельным аспектам нейровоспаления, в то время как апоптоз глии остается малоизученным. Цель исследования -оценить нейрональный и глиальный апоптоз в сопряжении с нейровоспалением в области эпилептического очага у пациентов с фокальной фармакорезистентной эпилепсией (ФРЭ). Материал и методы. Изучены биоптаты коры и белого вещества височной доли головного мозга от 30 пациентов с фокальной ФРЭ, обусловленной фокальной кортикальной дисплазией. Оценены патологические изменения и структурные признаки апоптоза, уровни апоптотических и провоспалительных факторов, таких как каспаза-3, каспаза-9, FAS, FAS-лиганд (FAS-L), фактор некроза опухоли α (ФНОα), p53, ядерный фактор κB (NF-κB). Использованы гистологические методы, трансмиссионная электронная микроскопия (ТЭМ), иммуногистохимическое исследование (ИГХ) и вестерн-блот (ВБ). Группу сравнения составил 21 человек без эпилепсии и поражения головного мозга. Результаты. ИГХ выявила экспрессию активной каспазы-3 в единичных нейронах (20% случаев) и в глиоцитах коры головного мозга и белого вещества (100% случаев) у пациентов с ФРЭ. При ТЭМ ультраструктурные признаки апоптоза обнаружены во всех случаях в нейронах и олигодендроцитах. ВБ эпилептического очага показал повышенную экспрессию факторов апоптоза каспазы-9, FAS, p53 и провоспалительных факторов ФНОα, NF-κB. Заключение. Полученные результаты указывают на наличие сопряженных процессов апоптоза и нейровоспаления при ФРЭ. Показано активное участие апоптоза глии в эпилептогенезе. Oсновную часть апоптотической глии составляют олигодендроциты, что объясняет известный феномен повреждения миелина при эпилепсии. Наряду с апоптозом нейронов, олигодендроцитарный апоптоз совместно с нейровоспалением формирует самоподдерживающийся патологический очаг, что способствует прогрессированию заболевания и возникновению рецидивов.