rmtОбщая реаниматологияGeneral Reanimatology1813-97792411-7110FSBI "SRIGR" RAMS10.15360/1813-9779-2019-5-11-22rmt-1814Research ArticleКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ И ПРАКТИКАCLINICAL STUDIES AND PRACTICEМолекулярные маркеры ишемического инсультаMolecular Markers of Ischemic StrokeГолубевА. М.GolubevA. M.

Россия, 107031, г. Москва, ул. Петровка, д. 25, стр. 2

Россия, 117198, г. Москва, ул. Миклухо-Маклая, д. 6

25 Petrovka Str., Bldg. 2, 107031 Moscow, Russia

6 Miklukho-Maсlaya Str., 117198 Moscow, Russia

arkadygolubev@mail.ruПетроваМ. В.PetrovaM. V.

Россия, 117198, г. Москва, ул. Миклухо-Маклая, д. 6

Россия, 141534, Московская область, Солнечногорский район, д. Лыткино, д. 777

6 Miklukho-Maсlaya Str., 117198 Moscow, Russia

777 Lytkino 141534, Solnechnogorsk district, Moscow region, Russia

ГречкоА. В.GrechkoA. V.

Россия, 141534, Московская область, Солнечногорский район, д. Лыткино, д. 777

777 Lytkino 141534, Solnechnogorsk district, Moscow region, Russia

ЗахарченкоВ. Е.ZakharchenkoV. E.

Россия, 141534, Московская область, Солнечногорский район, д. Лыткино, д. 777

777 Lytkino 141534, Solnechnogorsk district, Moscow region, Russia

КузовлевА. Н.KuzovlevA. N.

Россия, 107031, г. Москва, ул. Петровка, д. 25, стр. 2

Россия, 127473, г. Москва, ул. Делегатская, д. 20, стр. 1

25 Petrovka Str., Bldg. 2, 107031 Moscow, Russia

20 Delegatskaya Str., Build 1, 127473 Moscow, Russia

ЕршовА. В.ErshovA. V.

Россия, 107031, г. Москва, ул. Петровка, д. 25, стр. 2

Россия, 119991, г. Москва, ул. Трубецкая, д. 8, стр. 2

25 Petrovka Str., Bldg. 2, 107031 Moscow, Russia

8 Trubetskaya Str., Bldg. 2, 119991 Moscow, Russia

НИИ общей реаниматологии им. В. А. Неговского ФНКЦ РР, Российский университет дружбы народовРоссияV. A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Peoples’ Friendship University of RussiaRussian FederationРоссийский университет дружбы народов, Федеральный научно-клинический центр реаниматологии и реабилитологииРоссияPeoples’ Friendship University of Russia, Federal Research and Clinical Center of Intensive Care Medicine and RehabilitologyRussian FederationФедеральный научно-клинический центр реаниматологии и реабилитологииРоссияFederal Research and Clinical Center of Intensive Care Medicine and RehabilitologyRussian FederationФедеральный научно-клинический центр реаниматологии и реабилитологииРоссияFederal Research and Clinical Center of Intensive Care Medicine and Rehabilitology,Russian FederationНИИ общей реаниматологии им. В. А. Неговского ФНКЦ РР, Московский государственный медико-стоматологический университет им. А. И. Евдокимова Минздрава РоссииРоссияV. A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, A. I. Evdokimov Moscow State University of medicine and dentistry, Ministry of Health of RussiaRussian FederationНИИ общей реаниматологии им. В. А. Неговского ФНКЦ РР, Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава РоссииРоссияV. A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, I. M. Sechenov First Moscow State Medical University, Ministry of Health of RussiaRussian Federation2019071120191551122Copyright © Голубев А.М., Петрова М.В., Гречко А.В., Захарченко В.Е., Кузовлев А.Н., Ершов А.В., 20192019Голубев А.М., Петрова М.В., Гречко А.В., Захарченко В.Е., Кузовлев А.Н., Ершов А.В.Golubev A.M., Petrova M.V., Grechko A.V., Zakharchenko V.E., Kuzovlev A.N., Ershov A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.reanimatology.com/rmt/article/view/1814

Цель — оценить клиническую значимость биологических маркеров ЦНС при ишемическом инсульте.Материал и методы. Методом иммуноферментного анализа провели количественную оценку содержания биомаркеров ЦНС в сыворотке крови пациентов с нарушениями мозгового кровообращения по ишемическому типу. Исследовали нейронспецифическую енолазу, нейротрофический фактор головного мозга (BDNF), глиальный нейротрофический фактор (GDNF), белок S-100 общий (ɑβ–ββ), сиалированный углеводный антиген (KL-6), васкулоэндотелиальный фактор роста, супероксиддисмутазу. Все исследования проводили на автоматическом микропланшетном иммуноферментном анализаторе Immunomat ТМ. Число пациентов с нарушениями мозгового кровообращения — 43 в возрасте от 50 до 80 лет. Из них женщин — 24, мужчин — 19. Содержание биомаркеров ЦНС в сыворотке крови исследовали в первые 3–6 часов, через 2, 3 и 4 недели от начала заболевания. Контрольную группу составили 20 добровольцев (практически здоровых доноров). Статистический анализ провели непараметрическим методом Манна–Уитни. Статистически значимые результаты учитывали при р 0,05.Результаты. В донекротический период и начало формирования некроза отмечали повышение содержания нейронспецифической енолазы, белка S-100, супероксиддисмутазы, снижение содержания нейротрофического фактора головного мозга, глиального нейротрофического фактора, отражающих процессы альтерации структур головного мозга в результате нарушений кровообращения. В последующие сроки наблюдения возрастало содержания нейротрофического фактора головного мозга, глиального нейротрофического фактора, фактора роста эндотелия сосудов, сиалированного углеводного антигена, что свидетельствовало об активизации процессов регенерации центральной нервной системы.Заключение. Содержание биологических маркеров в сыворотке крови пациентов с ишемическим инсультом отражает этапы заболевания и позволяет контролировать процессы регенерации ЦНС.

The purpose of the study was to evaluate the clinical significance of CNS biological markers in an ischemic stroke.Materials and methods. Blood serum biomarkers of CNS were assayed by ELISA in patients suffering from cerebrovascular disorders of ischemic origin. Neuron-specific enolase, brain-derived neutrophic factor (BDNF), glial-derived neutrophic factor (GDNF), protein S-100 total (ɑβ–ββ), sialyl carbohydrate antigen (KL-6), vascular endothelial growth factor, and superoxide dismutase were analyzed. All tests were carried out using automatic microplate immunoassay analyzer Immunomat TM. The study included 43 patients of 50 to 80 years of age, suffering from cerebrovascular disorders; among them there were 24 women and 19 men. Blood serum biomarkers of CNS were assayed within the first 3–6 hours, and on week 2, 3, and 4 from onset of the disease. The control group consisted of 20 volunteers (apparently healthy donors). Statistical analysis was carried out using non-parametrical Mann–Whitney test. Results were considered as significant at P 0.05.Results. During the pre-necrotic and early necrotic period, higher neuron-specific enolase, protein S-100, superoxide dismutase, and lower brain-derived neutrophic factor and glial-derived neutrophic factor were observed, reflecting structural brain alterations due to disturbed circulation. At later follow-up time-points, BDNF, GDNF, VEGF, and KL-6 increased evidencing activated CNS regeneration processes.Conclusion. The content of biological markers in blood serum of ischemic stroke patients reflects the disease stages, which helps managing the CNS regeneration processes.

ишемический инсультмолекулярные маркерыischemic strokemolecular markersReferencesSonderer J., Katan Kahles M. Aetiological blood biomarkers of ischemic stroke. Swiss Med. Wkly. 2015; 145: w14138. PMID: 26024210. DOI: 10.4414/smv.2015.14138.Sonderer J., Katan Kahles M. Aetiological blood biomarkers of ischemic stroke. Swiss Med. Wkly. 2015; 145: w14138. PMID: 26024210. DOI: 10.4414/smv.2015.14138.Monbailliu T., Goossens J., Hachimi-Idrissi S. Blood protein biomarkers tool for ischemic stroke: a systematic review. Biomark. Med. 2017; 11 (6): 503–512. DOI:10.2217/bmm-2016-0232.Monbailliu T., Goossens J., Hachimi-Idrissi S. Blood protein biomarkers tool for ischemic stroke: a systematic review. Biomark. Med. 2017; 11 (6): 503–512. DOI: 10.2217/bmm-2016-0232.Misra S., Kumar A., Kumar P., Yadav A.K., Mohania D., Pandit A.K., Prasad K., Vibha D. Blood-based protein biomarkers for stroke differentiation: A systematic review/ Proteomics Clin. Appl. 2017; 11 (9–10). DOI: 10.1002/prca.201700007.Misra S., Kumar A., Kumar P., Yadav A.K., Mohania D., Pandit A.K., Prasad K., Vibha D. Blood-based protein biomarkers for stroke differentiation: A systematic review/ Proteomics Clin. Appl. 2017; 11 (9-10). DOI: 10.1002/prca.201700007.Ng G.J.L., Quek A.M.L., Cheung C., Arumugam T.V., Seet R.C.S. Stroke biomarkers in clinical practice: A critical appraisal. Neurochem Int. 2017; 107: 11–22. DOI: 10.1016/j.neuint.2017.01.005.Ng G.J.L., Quek A.M.L., Cheung C., Arumugam T.V., Seet R.C.S. Stroke biomarkers in clinical practice: A critical appraisal. Neurochem Int. 2017; 107: 11–22. DOI: 10.1016/j.neuint.2017.01.005.Stanca D.M., Marginean I.C., Soritau O., Muresanu D.F. Plasmatic markers for early diagnostic and treatment decisions in ischemic stroke. J. Med. Life. 2015; 8: 21–25. PMID: 26366222. PMCID: PMC4564040.Stanca D.M., Marginean I.C., Soritau O., Muresanu D.F. Plasmatic markers for early diagnostic and treatment decisions in ischemic stroke. J. Med. Life. 2015; 8: 21–25. PMID: 26366222. PMCID: PMC4564040.Lu G., He Q., Shen Y., Cao F. Potential biomarkers for predicting hemorrhagic transformation of ischemic stroke. Int. J. Neurosci. 2018; 128 (1): 79–89. DOI: 10.1080/00207454.2017.1349766.Lu G., He Q., Shen Y., Cao F. Potential biomarkers for predicting hemorrhagic transformation of ischemic stroke. Int. J. Neurosci. 2018; 128 (1): 79–89. DOI: 10.1080/00207454.2017.1349766.Голубев А.М., Кузовлев А.Н., Антонова В.В., Захарченко В.Е., Петрова М.В., Гречко А.В. Молекулярные биомаркерыGolubev A.M., Kuzovlev A.N., Antonova V.V., Zakharchenko V.E., Petrova M.V., Grechko A.V. Molecular Biomarkers for Prediction of Neurological Outcome after Sudden Circulatory Arrest (Review). Obschaya reanimatilogiya = General Reanimatology. 2018; 14 (3): 68–81. [In Russ.] https://doi.org/10.15360/1813-9779-2018-3-68-81прогнозирования неврологического исхода после внезапной остановки кровообращения (обзор). Общая реаниматология. 2018; 14 (3): 68–81. DOI: 10.15360/1813-9779-2018-3-68-81.Jolana L., Kamil D. The Role microRNA in ischemic and Hemorrhagic Stroke. Curr. Drug Deliv. 2017; 14 (6): 816–831. DOI: 10.2174/1567201813666160919142212.Jolana L., Kamil D. The Role microRNA in ischemic and Hemorrhagic Stroke. Curr. Drug Deliv. 2017; 14 (6): 816–831. DOI: 10.2174/1567201813666160919142212.Chen W., Sinha B., Benowitz L., Chen Q., Zhang Z., Patel N.J., Aziz-Sultan A.M., Chiocca A.E., Wang X. Monogenic, Polygenic R.N.A., Micro R.N.A. Markers for Ischemic stroke. Mol. Neurobiol. 2019; 56 (2): 1330–1343. DOI: 10.1007/s12035-018-1055-3.Chen W., Sinha B., Benowitz L., Chen Q., Zhang Z., Patel N.J., Aziz-Sultan A.M., Chiocca A.E., Wang X. Monogenic, Polygenic R.N.A., Micro R.N.A. Markers for Ischemic stroke. Mol. Neurobiol. 2019; 56 (2): 1330–1343. DOI: 10.1007/s12035-018-1055-3.Branco J.P., Costa J.S., Sargento-Freitas J., Oliveira S., Mendes B., Lains J., Pinheiro J. Neuroimaging and Blood Biomarkers in Functional Prognosis after Stroke. Acta Med. Port. 2016; 29 (11): 749–754. DOI: 10.20344/amp.7411.Branco J.P., Costa J.S., Sargento-Freitas J., Oliveira S., Mendes B., Lains J., Pinheiro J. Neuroimaging and Blood Biomarkers in Functional Prognosis after Stroke. Acta Med. Port. 2016; 29 (11): 749–754. DOI: 10.20344/amp.7411.Makris K., Haliassos A., Chondrogianni M., Tsivgoulis G. Blood biomarkers in ischemic stroke: potential role and challenges in clinical practice and research. Crit. Rev. Clin. Lab. Sci. 2018; 55 (5): 294–328. DOI: 10.1080/10408363.2018.1461190.Makris K., Haliassos A., Chondrogianni M., Tsivgoulis G. Blood biomarkers in ischemic stroke: potential role and challenges in clinical practice and research. Crit. Rev. Clin. Lab. Sci. 2018; 55 (5): 294–328. DOI: 10.1080/10408363.2018.1461190.Zaheer S., Beg M., Rizvi I., Islam N., Ullah E., Akhtar N. Correlation between serum neuron specific enolase and functional neurological outcome in patients of acute ischemic stroke. Ann. Indian Acad. Neurol. 2013; 16 (4): 504–508. DOI: 10.4103/0972-2327.120442.Zaheer S., Beg M., Rizvi I., Islam N., Ullah E., Akhtar N. Correlation between serum neuron specific enolase and functional neurological outcome in patients of acute ischemic stroke. Ann. Indian Acad. Neurol. 2013; 16 (4): 504–508. DOI: 10.4103/0972-2327.120442.Kim B.J., Kim Y.J., Ahn S.H., Kim N.Y., Kang D.W., Kim J.S., Kwon S.U. The second elevation of neuron-specific enolase peak after ischemic stroke is associated with hemorrhagic transformation. J. Stroke Cerebrovasc. Dis. 2014; 23 (9): 2437–2443. DOI: 10.1016/j.jstrokectrebrovasdis.2014.05.020.Kim B.J., Kim Y.J., Ahn S.H., Kim N.Y., Kang D.W., Kim J.S., Kwon S.U. The second elevation of neuron-specific enolase peak after ischemic stroke is associated with hemorrhagic transformation. J. Stroke Cerebrovasc. Dis. 2014; 23 (9): 2437–2443. DOI: 10.1016/j.jstrokectrebrovasdis.2014.05.020.Lu K., Xu X., Cui S., Wang F., Zhang B., Zhao Y. Serum neuron specific enolase level as a predictor of prognosis in acute ischemic stroke patients after intravenous thrombolysis. J. Neurol. Sci. 2015; 359 (1–2): 202–206. DOI: 10.1016/j.jns.2015.10.034.Lu K., Xu X., Cui S., Wang F., Zhang B., Zhao Y. Serum neuron specific enolase level as a predictor of prognosis in acute ischemic stroke patients after intravenous thrombolysis. J. Neurol. Sci. 2015; 359 (1–2): 202–206. DOI: 10.1016/j.jns.2015.10.034.Isgro M.A., Bottoni P., Scatena R. Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects. Adv. Exp. Med. Biol. 2015; 867: 125–143. DOI: 10.1007/978-94-017-7215-0_9.Isgro M.A., Bottoni P., Scatena R. Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects. Adv. Exp. Med. Biol. 2015; 867: 125–143. DOI: 10.1007/978-94-017-7215-0_9.Gonzalez-Quevedo A., Gonsalez-Garcia S., Hernandez-Diaz Z., Fernandez Concepcion O., Fernandez-Flvirall I., Menendez-Sainz MC., Fernandez-Carriera R. Serum neuron specific enolase could predict subclinical brain damage and the subsequent occurence of brain related vascular events during follow up in essential hypertension. J. Nturol. Sci. 2016; 363: 158–163. DOI: 10.1016/j.jns.2016.02.052.Gonzalez-Quevedo A., Gonsalez-Garcia S., Hernandez-Diaz Z., Fernandez Concepcion O., Fernandez-Flvirall I., Menendez-Sainz MC., Fernandez-Carriera R. Serum neuron specific enolase could predict subclinical brain damage and the subsequent occurence of brain related vascular events during follow up in essential hypertension. J. Nturol. Sci. 2016; 363: 158–163. DOI: 10.1016/j.jns.2016.02.052.Haupt W.F., Chopan G., Sobesky J., Liu W.C., Dohmen C. Prognostic value of somatostnsory evoked potentials, neuron-specific enolase? And S100 for short-term outcome in ischemic stroke. J.Neurophysiol. 2016; 115 (3): 1273–1278. DOI: 10.1152/jn.01012.2015.Haupt W.F., Chopan G., Sobesky J., Liu W.C., Dohmen C. Prognostic value of somatostnsory evoked potentials, neuron-specific enolase? And S100 for short-term outcome in ischemic stroke. J. Neurophysiol. 2016; 115 (3): 1273–1278. DOI: 10.1152/jn.01012.2015.Ostrova I.V., Avrushchenko M.S., Golubev A.M., Golubeva N.V. The Contribution of Brain-Derived Neurotrophic Factor (BDNF) and its TrkB Receptor to Hippocampal Neuron Resistance to Ischemia-Reperfusion (Experimental Study). Obshaya Reanimatologiya=General Reanimatology. 2018; 14 (6): 41–50. [In Russ.] DOI: 10.15360/1813-9779-2018-6-41-50Острова И.В., Аврущенко М.Ш., Голубев А.М., Голубева Н. В. Роль мозгового нейротрофического фактора BDNF и его рецептора TrkB в устойчивости нейронов гиппокампа к ишемии-реперфузии (экспериментальное исследование). Общая реаниматология. 2018. 14 (6): 41–50. DOI: 10.15360/1813-9779-2018-6-41-50.Qiao H.J., Li Z.Z., Wang L.M., Sun W., Yu J.C., Wang B. Association of lower serum Brain-derived neurotrophic factor levels with larger infarct volumes in acute ischemic stroke. J. Neuroimmunol. 2017; 307: 69–73. DOI: 10.1016/j.jneuroim.2017.04.002.Qiao H.J., Li Z.Z., Wang L.M., Sun W., Yu J.C., Wang B. Association of lower serum Brain-derived neurotrophic factor levels with larger infarct volumes in acute ischemic stroke. J. Neuroimmunol. 2017; 307: 69–73. DOI: 10.1016/j.jneuroim.2017.04.002.Casas S., Perez A.F., Mattiazzi M., Lopez J., Folgueira A., Gargiulo-Monachelli G.M. Potential Biomarkers with Plasma Cortisol, Brainderived Neurotrophic Factor and Nitrites in Patients with Acute Ischemic Snroke. Curr. Neurovasc. Res. 2017; 14 (4): 338–346. DOI: 10.2174/1567202614666171005122925.Casas S., Perez A.F., Mattiazzi M., Lopez J., Folgueira A., Gargiulo-Monachelli G.M. Potential Biomarkers with Plasma Cortisol, Brainderived Neurotrophic Factor and Nitrites in Patients with Acute Ischemic Snroke. Curr. Neurovasc. Res. 2017; 14 (4): 338–346. DOI: 10.2174/1567202614666171005122925.Xu H.B., Xu Y.H., He Y., Xue F., Wei J., Zhang Y., Wu J. Decreased Serum Brain-Derived Neurotrophic May Indicate the Development of Poststroke Depression in Patients with Acute Ischemic Stroke: A Meta-Analisis. J. Stroke Ctrebrovasc. Dis. 2018; 27 (3): 709–715. DOI: 10.1016/j.jstrokectrebrovasdis.2017.10.003.Xu H.B., Xu Y.H., He Y., Xue F., Wei J., Zhang Y., Wu J. Decreased Serum Brain-Derived Neurotrophic May Indicate the Development of Poststroke Depression in Patients with Acute Ischemic Stroke: A Meta-Analisis. J. Stroke Ctrebrovasc. Dis. 2018; 27 (3): 709–715. DOI: 10.1016/j.jstrokectrebrovasdis.2017.10.003.Bao M.H., Zhu S.Z., Gao X.Z., Sun H.S., Feng Z.P. Meta-Analysis on the Association between Brain-Derived Neurotrophic Factor Polymorphism rs6265 and ischemic Stroke, Poststroke Depression. J. Stroke Ctrebrovasc. Dis. 2018; 27 (6): 1599–1608. DOI: 10.1016/j.jstrokectrebrovasdis.2018.01.010.Bao M.H., Zhu S.Z., Gao X.Z., Sun H.S., Feng Z.P. Meta-Analysis on the Association between Brain-Derived Neurotrophic Factor Polymorphism rs6265 and ischemic Stroke, Poststroke Depression. J. Stroke Ctrebrovasc. Dis. 2018; 27 (6): 1599–1608. DOI: 10.1016/j.jstrokectrebrovasdis.2018.01.010.Zhou J., Ma M.M., Fang J.H., Zhao L., Zhou V.K., Guo J., He L. Differences in drain-derived neurotrophic factor gene polymorphisms between acute ischemicstroke patients and healthy controls in the Han population of southwest China. Neural Regen Res. 2019; 14 (8): 1404–1411. DOI: 10.4103/1673-5374.253525.Zhou J., Ma M.M., Fang J.H., Zhao L., Zhou V.K., Guo J., He L. Differences in drain-derived neurotrophic factor geneKeshavarz P., Saberi A., Sharafshah A., Asgari K.,Rezaei S. Association of BDNF G196A Gene Polymorphism with Ischemic Stroke Occurrence and its 6-Month Outcome in an Iranian Population. Top Stroke Rehabil. 2016; 23 (4): 254–260. DOI: 10.1080/10749357.2016.1141491.polymorphisms between acute ischemicstroke patients and healthy controls in the Han population of southwest China. Neural Regen Res. 2019; 14(8): 1404–1411. DOI: 10.4103/1673-5374.253525.Luo W., Liu T., Li S., Wen H., Zhou F., Zafonte R., Luo X., Xu M., Black-Schaffer R., Wood L., Wang Y., Wang Q.M. The Serum BDNF Level Offers Minimum Predictive Value for Motor Function Recovery After Stroke. Transl Stroke Res. 2019; 10 (4): 342-351. DOI: 10.1007/s12975-018-0648-5.Keshavarz P., Saberi A., Sharafshah A., Asgari K.,Rezaei S. Association of BDNF G196A Gene Polymorphism with Ischemic Stroke Occurrence and its 6-Month Outcome in an Iranian Population. Top Stroke Rehabil. 2016; 23 (4): 254–260. DOI: 10.1080/10749357.2016.1141491.Pedard M., Breniere C., Pernet N., Vergely C., Bejot Y., Marie C. Brainderived neurotrophic factor in peripheral blood mononuclear cells and stroke outcome. Exp. Biol. Med. 2018; 24: 15353702188115612. DOI: 10.1117/15353702188115612.Luo W., Liu T., Li S., Wen H., Zhou F., Zafonte R., Luo X., Xu M., Black-Schaffer R., Wood L., Wang Y., Wang Q.M. The Serum BDNF Level Offers Minimum Predictive Value for Motor Function Recovery After Stroke. Transl Stroke Res. 2019; 10 (4): 342–351. DOI: 10.1007/s12975-018-0648-5.Mourao A.M., Vicente L.C.C., Abreu M.N.S., Vale Sant’Anna R., Vieira ELM., de Souza L.C., de Miranda A.S., Rachid M.A., Teixeira A.L. Plasma Levels of Brain-Derived Neurotrophic Factor are Associated with Prognosis in the Acute Phase of Ischemic Stroke. J. Stroke Ctrebrovasc. Dis. 2019; 28 (3): 735–740. DOI: 10.1016/j.jstrokectrebrovasdis.2018.11.013.Pedard M., Breniere C., Pernet N., Vergely C., Bejot Y., Marie C. Brainderived neurotrophic factor in peripheral blood mononuclear cells and stroke outcome. Exp. Biol. Med. 2018; 24: 15353702188115612. DOI: 10.1117/15353702188115612.Algin A., Erdogan V., Aydin I., Poyraz MK., Sirik M. Clinical usefulness of brain-derived neurotrophic factor ana visinin-like protein-1 in early diagnostic tests for acute stroke. Am. J. Emerg. Med. 2019; pii: SO735-6757 (19)30124-X. DOI: 10.1016/j.ajem.2019.02.037.Mourao A.M., Vicente L.C.C., Abreu M.N.S., Vale Sant’Anna R., Vieira ELM., de Souza L.C., de Miranda A.S., Rachid M.A., Teixeira A.L. Plasma Levels of Brain-Derived Neurotrophic Factor are Associated with Prognosis in the Acute Phase of Ischemic Stroke. J. Stroke Ctrebrovasc. Dis. 2019; 28 (3): 735–740. DOI: 10.1016/j.jstrokectrebrovasdis.2018.11.013.Tejeda G.S., Esteban-Ortega G.M., San Antonio E., Vidaurre O.G. Prevention of exitotoxicity-induced processing of BDNF receptor TrkBFL leads to stroke neuroprotection. EMBO Mol. Med. 2019; 11 (7): e9950. DOI: 10.15252/emmm.201809950.Algin A., Erdogan V., Aydin I., Poyraz MK., Sirik M. Clinical usefulness of brain-derived neurotrophic factor ana visinin-like protein-1 in early diagnostic tests for acute stroke. Am. J. Emerg. Med. 2019; pii: SO735-6757(19)30124-X. DOI: 10.1016/j.ajem.2019.02.037.Lasek-Bal A., Jedrzejowska-Scypulka H., Rozicka J., Holecki M., Dulawa J., Lewin-Kowalik J. Low Concentration of BDNF in the Acute Phase ischemic Stroke as a Factor in Poor Prognosis in Terms of Functional Status of Patients. Med. Sci. Monit. 2015; 21: 3900–3905. DOI: 10.12659/MSM.895358Tejeda G.S., Esteban-Ortega G.M., San Antonio E., Vidaurre O.G. Prevention of exitotoxicity-induced processing of BDNF receptor TrkBFL leads to stroke neuroprotection. EMBO Mol. Med. 2019; 11 (7): e9950. DOI: 10.15252/emmm.201809950.Ramagiri S., Taliyan R. Remote limb ischemic post conditioning during early reperfusion alleviates certebral ischemic reperfusion injury vita GSK-3β/CREB/BDNF pathway. Eur. J. Pharmacol. 2017; 803: 84–93. DOI: 10.1016/j.ejphar.2017.03.028.Lasek-Bal A., Jedrzejowska-Scypulka H., Rozicka J., Holecki M., Dulawa J., Lewin-Kowalik J. Low Concentration of BDNF in the Acute Phase ischemic Stroke as a Factor in Poor Prognosis in Terms of Functional Status of Patients. Med. Sci. Monit. 2015; 21: 3900–3905. DOI:He Y., Cai Z., Chen Y. Role of S-100β in stroke. Int. J. Neurosci. 2018; 128 (12): 1180–1187. DOI: 10.1080/00207454.2018.1481065.12659/MSM.895358Böttner T., Weyers S., Postert T., Sprengelmeyer R., Kuhn W. S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke. 1997; 28 (10): 1961–1965. DOI: 10.1161/01.STR.28.10.1961Ramagiri S., Taliyan R. Remote limb ischemic post conditioning during early reperfusion alleviates certebral ischemic reperfusion injury vita GSK-3β/CREB/BDNF pathway. Eur. J. Pharmacol. 2017; 803: 84–93. DOI: 10.1016/j.ejphar.2017.03.028.Zhou S., Bao J., Wang Y., Pan S. S100β as a diomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke. Neurol. Res. 2016; 38 (4): 327–332. DOI: 10.1080/01616412.2016.1152675.He Y., Cai Z., Chen Y. Role of S-100β in stroke. Int. J. Neurosci. 2018; 128 (12): 1180–1187. DOI: 10.1080/00207454.2018.1481065.Branco J.P., Oliveira S., Sargento-Freitas J., Santos Costa J., Cordeiro G., Cunha L., Freire Goncalves A., Pinheiro J. S100β Protein as a Predictor of Poststroke Functional Outcome: A Prospective Study. J. Stroke Ctrebrovasc. Dis. 2018; 27 (7): 1890–1896. DOI: 10.1016/j.jsrokectrebrjvasdis.2018.02.046.Böttner T., Weyers S., Postert T., Sprengelmeyer R., Kuhn W. S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke. 1997; 28(10): 1961–1965. DOI: 10.1161/01.STR.28.10.1961Wang Y., Chang C.F., Morales M., Chiang Y.H., Hoffer J.P. Protective effects of glial cell line-derived neurotrophic factor in ischemic brain injury. Ann. N.Y.Acad. Sci. 2002; 962: 423–437.Zhou S., Bao J., Wang Y., Pan S. S100β as a diomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke. Neurol. Res. 2016; 38 (4): 327–332. DOI: 10.1080/01616412.2016.1152675.Matsuo R., Ago T., Kamouchi M.,Kuroda J., Kuwashiro T., Hata J., Sugimori H., Fukuda K., Gotoh S., Makihara N., Fukuhara M., Awano H., Isomura T., Suzuki K., Yasaka M., Okada Y., Kiyphara Y., Kitazono T. Clical significance of plasma VEGF value in ischemic stroke – research for biomarkers I ischemic stroke (REBIOS) study. BMC Neurol. 2013; 13: 32. DOI: 10.1186/1471-2377-13-32.Branco J.P., Oliveira S., Sargento-Freitas J., Santos Costa J., Cordeiro G., Cunha L., Freire Goncalves A., Pinheiro J. S100β Protein as a Predictor of Poststroke Functional Outcome: A Prospective Study. J. Stroke Ctrebrovasc. Dis. 2018; 27 (7): 1890–1896. DOI: 10.1016/j.jsrokectrebrjvasdis.2018.02.046.Geiseler S.J., Morland C. The Janus Face of VEGF in Stroke. Int. J. Mol. Sci. 2018; 19 (5). Pii: 1362. DOI: 10.3390/ijms190511362.Wang Y., Chang C.F., Morales M., Chiang Y.H., Hoffer J.P. Protective effects of glial cell line-derived neurotrophic factor in ischemic brain injury. Ann. N.Y.Acad. Sci. 2002; 962: 423–437.Jean LeBlanc N., Guruswamy R., ElAli A. Vascular Endothelial Growth Factor Isoform-B Stimulates Neurovascular Repair After Ischemic Stroke by Promoting the Functijn of Pericytes via Vascular Endothelial Growth Factor Receptor-1. Mol. Neurobiol. 2018; 55 (5): 3611–3626. DOI: 10.1007/s12035-017-0478-6.Matsuo R., Ago T., Kamouchi M.,Kuroda J., Kuwashiro T., Hata J., Sugimori H., Fukuda K., Gotoh S., Makihara N., Fukuhara M., Awano H., Isomura T., Suzuki K., Yasaka M., Okada Y., Kiyphara Y., Kitazono T. Clical significance of plasma VEGF value in ischemic stroke – research for biomarkers I ischemic stroke (REBIOS) study. BMC Neurol. 2013; 13: 32. DOI: 10.1186/1471-2377-13-32.Setyopranoto I., Sadeva A.H., Wibowo S., Widyadharma I.P.E. Comparison of Mean VEGF-A Expression Between Acute Ischemic Stroke Patients and Non-ischemic Stroke. Open Access Maced J. Med. Sci. 2019; 7 (5): 747–751. DOI: 10.3889/oamjms.2019.175.Geiseler S.J., Morland C. The Janus Face of VEGF in Stroke. Int. J. Mol. Sci. 2018; 19 (5). Pii: 1362. DOI: 10.3390/ijms190511362.Davis S.M., Pennypacker K.R. Targeting antioxidant enzyme expression as atherapeutic strategy for ischemic stroke. Neurochem int. 2017; 107: 23–32. DOI: 10.1016/j.neuint.2016.12.007.Jean LeBlanc N., Guruswamy R., ElAli A. Vascular Endothelial Growth Factor Isoform-B Stimulates Neurovascular Repair After Ischemic Stroke by Promoting the Functijn of Pericytes via Vascular Endothelial Growth Factor Receptor-1. Mol. Neurobiol. 2018; 55 (5): 3611–3626. DOI: 10.1007/s12035-017-0478-6.Dayal S., Baumbach G.L., Arning E., Bottiglieri T., Faraci F.M., Lentz S.R. Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia. PLoS One. 2017; 12 (4): e0175732. DOI: 10.1371/journal.pone.0175732.Setyopranoto I., Sadeva A.H., Wibowo S., Widyadharma I.P.E. Comparison of Mean VEGF-A Expression Between Acute Ischemic Stroke Patients and Non-ischemic Stroke. Open Access Maced J. Med. Sci. 2019; 7 (5): 747–751. DOI: 10.3889/oamjms.2019.175.Liu Z., Cai Y., Zhang X., Zhu Z., He J. High serum levels of malondialdehyde and antioxidant enzymes are assopciated with post-stroke anxiety. Neurol. Sci. 2018; 39 (6): 999–1007. DOI: 10.1007/s10072-018-3287-4.Davis S.M., Pennypacker K.R. Targeting antioxidant enzyme expression as atherapeutic strategy for ischemic stroke. Neurochem int. 2017; 107: 23–32. DOI:10.1016/j.neuint.2016.12.007.Schnaar R.L., Gerardy-Schahn R., Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol. Rev. 2014; 94 (2): 461-518. DOI: 10.1152/phisrev.00033.2013.Dayal S., Baumbach G.L., Arning E., Bottiglieri T., Faraci F.M., Lentz S.R. Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia. PLoS One. 2017; 12 (4): e0175732. DOI: 10.1371/journal.pone.0175732.Linnartz-Gerlach B., Mathews M., Neumann H. Sensing the neuronal glycocalyx by glial sialic acid binding immunoglobulin-like lectins. Neuroscience. 2014; 275: 113–124. DOI: 10.1016/j.neuroscience.2014.05.061.Liu Z., Cai Y., Zhang X., Zhu Z., He J. High serum levels of malondialdehyde and antioxidant enzymes are assopciated with post-stroke anxiety. Neurol. Sci. 2018; 39 (6): 999–1007. DOI: 10.1007/s10072-018-3287-4.Linnartz B., Neumann H. Microglial activatore (immunoreceptor tyrosine-based activation motif)- and inhibitory (immunoreceptor tyrosine-based inhibition motif)-signaling receptors for recognition of the neuronal glycocalyx). Glia. 2013; 61 (1): 37–46. DOI: 10.1002/glia.22359.Schnaar R.L., Gerardy-Schahn R., Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol. Rev. 2014; 94 (2): 461–518. DOI:10.1152/phisrev.00033.2013.Schnaar R.L., Gerardy-Schahn R., Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol. Rev. 2014; 94 (2): 461–518. DOI:10.1152/phisrev.00033.2013.Linnartz-Gerlach B., Mathews M., Neumann H. Sensing the neuronal glycocalyx by glial sialic acid binding immunoglobulin-like lectins. Neuroscience. 2014; 275: 113-124. DOI: 10.1016/j.neuroscience.2014.05.061.Linnartz-Gerlach B., Mathews M., Neumann H. Sensing the neuronal glycocalyx by glial sialic acid binding immunoglobulin-like lectins. Neuroscience. 2014; 275: 113-124. DOI: 10.1016/j.neuroscience.2014.05.061.Linnartz B., Neumann H. Microglial activatore (immunoreceptor tyrosine-based activation motif)- and inhibitory (immunoreceptor tyrosine-based inhibition motif)-signaling receptors for recognition of the neuronal glycocalyx). Glia. 2013; 61(1): 37–46. DOI: 10.1002/glia.22359.Linnartz B., Neumann H. Microglial activatore (immunoreceptor tyrosine-based activation motif)- and inhibitory (immunoreceptor tyrosine-based inhibition motif)-signaling receptors for recognition of the neuronal glycocalyx). Glia. 2013; 61(1): 37–46. DOI: 10.1002/glia.22359.

The authors declare that there are no conflicts of interest present.