sechenovSechenov Medical JournalСеченовский вестник2218-73322658-3348Сеченовский Университет10.47093/2218-7332.2021.12.4.39-50sechenov-415Research ArticleNEUROSURGERYНЕЙРОХИРУРГИЯCytokine profile in the peripheral blood and the brain in patients with focal drug-resistant epilepsyИсследование цитокинового профиля в периферической крови и головном мозге у пациентов с фокальной фармакорезистентной эпилепсиейhttps://orcid.org/0000-0001-9721-3827СитовскаяД. А.SitovskaiaD. A.

врач-патологоанатом, научный сотрудник научно-исследовательскойлаборатории патоморфологии нервной системы; ассистент кафедры патологической анатомии 

Tel.: +7 (981) 761-31-97 

ул. Маяковского, д. 12, Санкт-Петербург, 191014, Россия

ул. Литовская, д. 2, Санкт-Петербург, 194100, Россия

 pathologist, researcher, Research Laboratory of Nervous System Pathomorphology; Assistant Professor, Department of Pathology 

 Tel.: +7 (981) 761-31-97 

12, Mayakovskogo str., Saint-Petersburg, 191014, Russia

2, Litovskaya str., Saint-Petersburg, 194100, Russia

https://orcid.org/0000-0002-7810-0832ЛитовченкоА. В.LitovchenkoA. V.

аспирант лаборатории сравнительной биохимии и клеточных функций 

пр. Тореза, д. 44, Санкт-Петербург, 194223, Россия

post-graduate student, Laboratory of Comparative Biochemistry and Cellular Functions

44, Toreza av., Saint-Petersburg, 194223, Russia

https://orcid.org/0000-0002-9763-504XБажановаЕ. Д.BazhanovaE. D.

 д-р мед. наук, ведущий научный сотрудник лаборатории сравнительной биохимии и клеточных функций; заведующая лабораторией морфологии и электронной микроскопии; старший научный сотрудник кафедры  биохимии 

пр. Тореза, д. 44, Санкт-Петербург, 194223, Россия

ул. Бехтерева, д. 1, Санкт-Петербург, 192019, Россия

ул. Татищева, д. 20а, Астрахань, 414000, Россия

 Dr. of Sci. (Med.), Leading Researcher, Laboratory of Comparative Biochemistry and Cellular Functions; Head of the Laboratory of Morphology and Electron Microscopy; Senior Researcher,  Department of Biochemistry

44, Toreza av., Saint-Petersburg, 194223, Russia

1, Bechtereva str., Saint-Petersburg, 192019, Russia 

 20a, Tatischeva str., Astrakhan, 414000, Russia 

https://orcid.org/0000-0001-7008-6389СкитеваЕ. Н.SkitevaE. N.

 младший научный сотрудник научно-исследовательской лаборатории патоморфологии нервной системы 

ул. Маяковского, д. 12, Санкт-Петербург, 191014, Россия

 junior researcher, Research Laboratory of Nervous System Pathomorphology

 12, Mayakovskogo str., Saint-Petersburg, 191014, Russia 

https://orcid.org/0000-0001-6206-2133ЗабродскаяЮ. М.ZabrodskaiaYu. M.

 д-р мед. наук, заведующая научно-исследовательской лабораторией патоморфологии нервной системы; ведущий научный сотрудник лаборатории морфологии и электронной микроскопии; доцент кафедры патологической анатомии 

ул. Маяковского, д. 12, Санкт-Петербург, 191014, Россия

ул. Бехтерева, д. 1, Санкт-Петербург, 192019, Россия

ул. Академика Лебедева, д. 6, Санкт-Петербург, 194044, Россия

 Dr. of Sci. (Med.), Head of the Research Laboratory of Nervous System Pathomorphology; Leading Researcher, Laboratory of Morphology and Electron Microscopy; Associate Professor, Department of Pathology

 12, Mayakovskogo str., Saint-Petersburg, 191014, Russia 

1, Bechtereva str., Saint-Petersburg, 192019, Russia

6, Academician Lebedev str., Saint-Petersburg, 194044, Russia

Российский научно-исследовательский нейрохирургический институт имени профессора А.Л. Поленова – филиал ФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Минздрава России; ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава РоссииРоссияPolenov Neurosurgical Institute – Branch of Almazov National Medical Research Centre; Saint Petersburg State Pediatric Medical UniversityRussian FederationФГБУН «Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН»РоссияSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesRussian FederationФГБУН «Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАН»; ГБУ «Научно-клинический центр токсикологии имени академика С.Н. Голикова ФМБА России»; ФГБОУ ВО «Астраханский государственный университет»РоссияSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences; Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency; Astrakhan State UniversityRussian FederationРоссийский научно-исследовательский нейрохирургический институт имени профессора А.Л. Поленова – филиал ФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Минздрава РоссииРоссияPolenov Neurosurgical Institute – Branch of Almazov National Medical Research CentreRussian FederationРоссийский научно-исследовательский нейрохирургический институт имени профессора А.Л. Поленова – филиал ФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Минздрава России; ФГБУ «Научно-клинический центр токсикологии имени академика С.Н. Голикова ФМБА России»; ФГБВОУ ВО «Военно-медицинская академия им. С.М. Кирова»РоссияPolenov Neurosurgical Institute – Branch of Almazov National Medical Research Centre; Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency; S.M. Kirov Military Medical AcademyRussian Federation202129112021124Special Issue "Neurosurgery"3950Copyright © Sitovskaia D.A., Litovchenko A.V., Bazhanova E.D., Skiteva E.N., Zabrodskaia Y.M., 20212021Ситовская Д.А., Литовченко А.В., Бажанова Е.Д., Скитева Е.Н., Забродская Ю.М.Sitovskaia D.A., Litovchenko A.V., Bazhanova E.D., Skiteva E.N., Zabrodskaia Y.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.sechenovmedj.com/jour/article/view/415

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.

Цель исследования. Изучить у пациентов с фармакорезистентной эпилепсией (ФРЭ) маркеры дисфункции гематоэнцефалического барьера (ГЭБ) – содержание VEGF в эндотелиоцитах капилляров мозга, TNF-α в ткани мозга и цитокиновый профиль в сыворотке крови.Материалы и методы. В исследование включены 30 пациентов с ФРЭ, которым проведена передняя темпоральная блок-резекция. Исследованы гистологические образцы головного мозга для оценки содержания VEGF и TNF-α; определена концентрация цитокинов в сыворотке крови.Результаты. В группе ФРЭ денситометрическая плотность клеток, экспрессирующих VEGF и содержание TNF-α в эпилептическом очаге, была выше, чем в контрольных группах (p < 0,001; p < 0,05). По сравнению с контролем в сыворотке крови пациентов с ФРЭ концентрация IL-2 (0,98 ± 0,28 против 2,80 ± 0,71 пг/мл; p < 0,001), IL-8 (14,04 ± 1,46 против 26,13 ± 3,80 пг/мл; p < 0,001) и EGF (43,72 ± 5,63 против 83,62 ± 24,06 пг/мл; p < 0,05) была статистически значимо ниже, а содержание TNF-α (33,09 ± 1,23 против 24,85 ± 1,32 пг/мл, p < 0,05), IL-4 (43,73 ± 2,57 против 32,37 ± 5,80 пг/мл, p < 0,05), IL-5 (43,73 ± 2,57 против 32,37 ± 5,80 пг/мл; p < 0,05), IL-7 (16,65 ± 3,07 против 8,13 ± 1,67 пг/мл; p < 0,05), GRO (growth-regulated protein) (3054,0 ± 200,8 против 1367,0 ± 187,3 пг/мл; p < 0,001), VEGF (316,10 ± 55,28 против 95,22 ± 15,78 пг/мл; p < 0,01) статистически значимо выше. Существенных различий по концентрации IL-1β, IL-1RA, IL-10 и IFN-γ между группами ФРЭ и контролем не установлено.Заключение. Исходя из изученного цитокинового профиля можно заключить, что у пациентов с ФРЭ отсутствует системное воспаление. Установленная гиперэкспрессия VEGF в головном мозге и увеличение концентрации его в крови в сочетании со снижением концентраций EGF в сыворотке крови и повышением GRO, а также провоспалительных факторов свидетельствует о повреждении ГЭБ. Высокое содержание TNF-α непосредственно в эпилептическом очаге свидетельствует о нейровоспалении, и в условиях дисфункции ГЭБ можно обнаружить повышенную концентрацию TNF-α в крови пациентов.

эпилепсиягематоэнцефалический барьерVEGFцитокинынейровоспалениеплотные контактыepilepsyblood-brain barrierVEGFcytokinesneuroinflammationtight junctionsИсследование цитокинов выполнено в рамках гранта РФФИ № 20-015-00127 и на оборудовании ЦКП ИЭФБ РАН. Иммуногистохимическое исследование проводилось в рамках Госзадания №121031000359-3 «Разработка новых подходов в диагностике медиобазальной фармакорезистентной эпилепсии на основе гистопротеомики эпилептических очагов».The study of citokines was carried out within the framework of the RFBR grant № 20-015-00127 and on the equipment of the CCU of the IEFB RAS. Immunohistochemical study was performed within the framework State task No. 121031000359-3 "Development of new approaches in the diagnosis of mediobasal pharmacoresistant epilepsy based on histoproteomics of epileptic foci".ReferencesSheng J., Liu S., Qin H., et al. Drug-Resistant epilepsy and surgery. 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The authors declare that there are no conflicts of interest present.