Bulletin of Rehabilitation MedicineBulletin of Rehabilitation MedicineВестник восстановительной медицины2078-19622713-2625National Medical Research Center for Rehabilitation and Balneology67654710.38025/2078-1962-2025-24-3-123-139ArticlesСтатьиReview ArticleNeurotrophic factors as markers of stroke recovery: a reviewНейротрофические факторы как маркеры восстановления после инсульта: обзорhttps://orcid.org/0000-0003-0629-9659KostenkoElena V.КостенкоЕлена Владимировна
Russian Federation

D.Sc. (Med.), Deputy Director for Scientific Work; Neurologist, Professor at the Department of Neurology, Neurosurgery and Medical Genetics

доктор медицинских наук, заместитель директора по научной работе; невролог, профессор кафедры неврологии, нейрохирургии и медицинской генетики

ludmila.v.petrova@yandex.ruhttps://orcid.org/0000-0003-0353-553XPetrovaLyudmila V.ПетроваЛюдмила Владимировна
Russian Federation

Ph.D. (Med.), Senior Researcher, Neurologist, Head of the Department of Medical Rehabilitation

кандидат медицинских наук, старший научный сотрудник, невролог, заведующий отделом медицинской реабилитации

ludmila.v.petrova@yandex.ruhttps://orcid.org/0000-0003-0238-1604EgorovPavel D.ЕгоровПавел Дмитриевич
Russian Federation

Junior Researcher

младший научный сотрудник

ludmila.v.petrova@yandex.ruhttps://orcid.org/0000-0001-5123-5991PogonchenkovaIrene V.ПогонченковаИрэна Владимировна
Russian Federation

D.Sc. (Med.), Associate Professor, Director

доктор медицинских наук, доцент, директор

ludmila.v.petrova@yandex.ruhttps://orcid.org/0000-0001-9522-5082FilippovMaxim S.ФилипповМаксим Сергеевич
Russian Federation

D.Sc. (Phys.), Head of Branch No. 3

заведующий филиалом № 3, врач физической реабилитационной медицины

ludmila.v.petrova@yandex.ruSpasokukotsky Moscow Centre for Research and Practice in Medical Rehabilitation, Restorative and Sports MedicineМосковский научно-практический центр медицинской реабилитации, восстановительной и спортивной медицины им С.И. СпасокукоцкогоPirogov Russian National Research Medical UniversityРоссийский национальный исследовательский медицинский университет им. Н.И. Пирогова090620252431231390303202502042025Copyright ©; 2025, Kostenko E.V., Petrova L.V., Egorov P.D., Pogonchenkova I.V., Filippov M.S.Copyright ©; 2025, Костенко Е.В., Петрова Л.В., Егоров П.Д., Погонченкова И.В., Филиппов М.С.2025Kostenko E.V., Petrova L.V., Egorov P.D., Pogonchenkova I.V., Filippov M.S.Костенко Е.В., Петрова Л.В., Егоров П.Д., Погонченкова И.В., Филиппов М.С.https://creativecommons.org/licenses/by/4.0https://journals.eco-vector.com/2078-1962/article/view/676547

INTRODUCTION. A review of studies on the role of neurotrophic factors: BDNF, NGF, BDNF, NGF, NT-3, NT-4/5, IGF-1 and other biomarkers, in predicting and enhancing ischemic stroke (IS) recovery is presented.

AIM. To analyze recent data on the role of neurotrophic factors in recovery processes post-stroke rehabilitation.

MAIN CONTENT OF THE REVIEW. High-level evidence-based works (randomized controlled trials, meta-analyses, systematic reviews) found in PubMed and Cochrane Library databases are included, ClinicalTrials.gov. for 2013–2025. The data on the importance of neurotrophic factors (NTF) in various periods of IS, as well as the effects of physical activity, genetic polymorphisms, and new therapeutic approaches aimed at increasing NTF levels are considered. NTFs have significant potential for predicting recovery outcomes and optimizing post-stroke rehabilitation.

CONCLUSION. Combining physical rehabilitation with pharmacological strategies targeting NTF mechanisms could lead to innovative therapies to improve stroke survivors’ quality of life.

ВВЕДЕНИЕ. Представлен обзор исследований, посвященных роли нейротрофических факторов (BDNF, NGF, GDNF, CNTF, NT-3, NT-4/5, IGF-1) и других биомаркеров в прогнозировании и улучшении восстановления после ишемического инсульта (ИИ).

ЦЕЛЬ. Проанализировать данные последних лет о роли нейротрофических факторов (НТФ) в восстановительных процессах после ИИ.

ОСНОВНОЕ СОДЕРЖАНИЕ ОБЗОРА. Включены работы высокого уровня доказательности (рандомизированные контролируемые исследования, метаанализы, систематические обзоры), найденные в базах данных PubMed, Cochrane Library, ClinicalTrials.gov. за 2013–2025 гг. Рассмотрены данные о значении НТФ в различные периоды ИИ, а также влияние физической активности, генетических полиморфизмов и новых терапевтических подходов, направленных на повышение уровней НТФ. Установлен высокий потенциал НТФ для прогнозирования исходов и в оптимизации восстановления после ИИ.

ЗАКЛЮЧЕНИЕ. Комбинация физической реабилитации с фармакологической модуляцией механизмов НТФ может стать основой новых терапевтических протоколов, улучшающих качество жизни пациентов после инсульта.

strokemedical rehabilitationfunctional outcomeneurotrophic factorsBDNFrisk factorsинсультмедицинская реабилитацияфункциональный исходнейротрофические факторыBDNFфакторы рискаДепартамент здравоохранения города МосквыMoscow City Department of Health123041200084-9Xing Y., Bai Y. A Review of Exercise-Induced Neuroplasticity in Ischemic Stroke: Pathology and Mechanisms. Mol Neurobiol. 2020; 57(11): 4218–4231. https://doi.org/10.1007/s12035-020-02021-1Skaper S. Neurotrophic Factors: An Overview. In: Skaper S., editor. Neurotrophic Factors: Methods and Protocols. New York, NY: Springer. 2018. p. 1–17. https://doi.org/10.1007/978-1-4939-7571-6_1Brunelli S., Giannella E., Bizzaglia M., et al. Secondary neurodegeneration following Stroke: what can blood biomarkers tell us? Front Neurol. 2023; 14: 1038808. https://doi.org/10.3389/fneur.2023.1198216He J., Chen L., Tang F., et al. Multidisciplinary team collaboration impact on NGF, BDNF, serum IGF-1, and life quality in patients with hemiplegia after stroke. Cell Mol Biol (Noisy-le-grand). 2023; 69(12): 57–64. https://doi.org/10.14715/cmb/2023.69.12.10Hernández-del Caño C., Varela-Andrés N., Cebrián-León A., Deogracias R. Neurotrophins and Their Receptors: BDNF’s Role in GABAergic Neurodevelopment and Disease. Int J Mol Sci. 2024; 25(15): 8312. https://doi.org/10.3390/ijms25158312Liu W., Wang X., O’Connor M., et al. Brain-derived neurotrophic factor and its potential therapeutic role in Stroke comorbidities. Neural Plast. 2020; 2020: 8107274. https://doi.org/10.1155/2020/1969482Sims-Knight C., Wilken-Resman B., Smith C., et al. Brain-Derived Neurotrophic Factor and Nerve Growth Factor Therapeutics for Brain Injury: The Current Translational Challenges in Preclinical and Clinical Research. Neural Plast. 2022; 2022: 9830128. https://doi.org/10.1155/2022/3889300Чуканова А.С., Гулиева М.Ш., Чуканова Е.И., Багманян С.Д. Применение сывороточных биомаркеров повреждения, апоптоза и нейротрофичности в оценке прогноза ишемического инсульта. Журнал неврологии и психиатрии им. С.С. Корсакова. Спецвыпуски. 2022; 122(8–2): 48–53. https://doi.org/10.17116/jnevro202212208248 [Chukanova A.S., Gulieva M.Sh., Chukanova E.I., Bagmanyan S.D. A panel of serum biomarkers, including damage, apoptosis and neurotrophic markers, for the assessment of prognosis of the course of ischemic stroke. S.S. Korsakov Journal of Neurology and Psychiatry. 2022; 122 (8–2): 48–53. https://doi.org/10.17116/jnevro202212208248 (In Russ.).]Shahnawaz A., Varun Kumar S., Varshaa Ch., Rameshwar Nath Ch. Neurorehabilitation and its relationship with biomarkers in motor recovery of acute ischemic stroke patients — A systematic review. J Clin Sci Res. 2024; 13(2):125. http://dx.doi.org/10.4103/jcsr.jcsr_16_23Ashcroft S., Ironside D., Johnson L., et al. Effect of Exercise on Brain-Derived Neurotrophic Factor in Stroke Survivors: A Systematic Review and Meta-Analysis. Stroke. 2022; 53(12): 3706–3716. https://doi.org/10.1161/strokeaha.122.039919Karantali E., Kazis D., Papavasileiou V., et al. Serum BDNF Levels in Acute Stroke: A Systematic Review and Meta-Analysis. Medicina (Kaunas). 2021; 57(3): 297. https://doi.org/10.3390/medicina57030297Mojtabavi H., Shaka Z., Momtazmanesh S., et al. Circulating brain-derived neurotrophic factor as a potential biomarker in stroke: a systematic review and meta-analysis. J Transl Med. 2022; 20(1): 233. https://doi.org/10.1186/s12967-022-03312-yZhou B., Mu K., Yu X., Shi X. Serum Levels and Clinical Significance of NSE, BDNF and CNTF in Patients with Cancer-associated Ischemic Stroke Complicated with Post-stroke Depression. Actas Esp Psiquiatr. 2024; 52(4): 474–483. https://doi.org/10.62641/aep.v52i4.1667Liu X., Fang J.-C., Zhi X.-Y., et al. The Influence of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor on Stroke Recovery Outcome: A Systematic Review and Meta-analysis. Neurorehabil Neural Repair. 2021; 35(6): 550–560. https://doi.org/10.1177/15459683211014119Santoro M., Siotto M., Germanotta M., et al. BDNF rs6265 Polymorphism and Its Methylation in Patients with Stroke Undergoing Rehabilitation. Int J Mol Sci. 2020; 21(22): 8438. https://doi.org/10.3390/ijms21228438Sukhan D., Liudkevych H., Olkhova I., et al. The role of neurotrophins in post-stroke rehabilitation. Rep Vinnytsia Nation Med Univ. 2021; 25(4): 651–656. https://doi.org/10.31393/reports-vnmedical-2021-25(4)-25Ledreux A., Håkansson K., Carlsson R., et al. Differential Effects of Physical Exercise, Cognitive Training, and Mindfulness Practice on Serum BDNF Levels in Healthy Older Adults: A Randomized Controlled Intervention Study. J Alzheimers Dis. 2019; 71(4): 1245–1261. https://doi.org/10.3233/JAD-190756Ploughman M., Eskes G., Kelly L., et al. Synergistic Benefits of Combined Aerobic and Cognitive Training on Fluid Intelligence and the Role of IGF-1 in Chronic Stroke. Neurorehabil Neural Repair. 2019; 33(3): 199–212. https://doi.org/10.1177/1545968319832605Björkholm C., Monteggia L. BDNF — a key transducer of antidepressant effects. Neuropharmacology. 2016; 102: 72–79. https://doi.org/10.1016/j.neuropharm.2015.10.034Cubillos S., Engmann O., Brancato A. BDNF as a Mediator of Antidepressant Response: Recent Advances and Lifestyle Interactions. Int J Mol Sci. 2022; 23(22): 14445. https://doi.org/10.3390/ijms232214445Brunello C., Cannarozzo C., Castrén E. Rethinking the role of TRKB in the action of antidepressants and psychedelics. Trends Neurosci. 2024; 47(11): 865–874. https://doi.org/10.1016/j.tins.2024.08.011Widodo J., Asadul A., Wijaya A., Lawrence G. Correlation between Nerve Growth Factor (NGF) with Brain Derived Neurotropic Factor (BDNF) in Ischemic Stroke Patient. Bali Med J. 2016; 5(2): 10. https://doi.org/10.15562/bmj.v5i2.199Li X., Li F., Ling L., et al. Intranasal administration of nerve growth factor promotes angiogenesis via activation of PI3K/Akt signaling following cerebral infarction in rats. Am J Transl Res. 2018; 10(11):3481–3492.Luan X., Qiu H., Hong X., et al. High Serum Nerve Growth Factor Concentrations Are Associated with Good Functional Outcome at 3 Months Following Acute Ischemic Stroke. Clinica Chimica Acta. 2019; 488: 20–24. https://doi.org/10.1016/j.cca.2018.10.030Gu C.-L., Ma L., Hou Y., et al. Exploring the Cellular and Molecular Basis of Nerve Growth Factor in Cerebral Ischemia Recovery. Neuroscience. 2024; 566: 190–197. https://doi.org/10.1016/j.neuroscience.2024.12.049Colitti N., Desmoulin F., Le Friec A., et al. Long-Term Intranasal Nerve Growth Factor Treatment Favors Neuron Formation in de Novo Brain Tissue. Front Cell Neurosci. 2022; 16: 871532. https://doi.org/10.3389/fncel.2022.871532Moghanlou A., Yazdanian M., Roshani S., et al. Neuroprotective effects of pre-ischemic exercise are linked to expression of NT-3/NT-4 and TrkB/TrkC in rats. Brain Res Bull. 2023; 194: 54–63. https://doi.org/10.1016/j.brainresbull.2023.01.004Chung J.-Y., Kim M.-W., Im W., et al. Expression of Neurotrophin-3 and TrkC Following Focal Cerebral Ischemia in Adult Rat Brain with Treadmill Exercise. J Korean Med Sci. 2017; 32(9): 1486–1492. https://doi.org/10.1155/2017/9248542Chung J.-Y., Kim M.-W., Bang M.-S., Kim M. Increased Expression of Neurotrophin 4 Following Focal Cerebral Ischemia in Adult Rat Brain with Treadmill Exercise. PLoS One. 2013; 8(3): e52461. https://doi.org/10.1371/journal.pone.0052461Cortés D., Carballo-Molina O., Castellanos-Montiel M., Velasco I. The Non-Survival Effects of Glial Cell Line-Derived Neurotrophic Factor on Neural Cells. Front Mol Neurosci. 2017; 10: 287. https://doi.org/10.3389/fnmol.2017.00258Zhang Z., Sun G., Ding S. Glial Cell Line-Derived Neurotrophic Factor and Focal Ischemic Stroke. Neurochem Res. 2021; 46(10): 2638–2650. https://doi.org/10.1007/s11064-021-03266-5Zhang N., Zhang Z., He R., et al. GLAST-CREERT2 Mediated Deletion of GDNF Increases Brain Damage and Exacerbates Long-Term Stroke Outcomes After Focal Ischemic Stroke in Mouse Model. Glia. 2020; 68(11): 2395–2414. https://doi.org/10.1002/glia.23848Куракина А.С., Семенова Т.Н., Щелчкова Н.А. и др. Прогностическая значимость определения уровня глиального нейротрофического фактора в плазме крови у больных с ишемическим инсультом. Пермский медицинский журнал. 2021; 38(2):95–102. https://doi.org/10.17816/pmj38295-102 [Kurakina A.S., Semenova T.N., Shchelchkova N A. et al. The prognostic significance of determining the level of glial neurotrophic factor in blood plasma in patients with ischemic stroke. Perm Medical Journal. 2021; 38(2): 95–102. https://doi.org/10.17816/pmj38295-102 (In Russ.).]Pasquin S., Sharma M., Gauchat J.-F. Cytokines of the LIF/CNTF Family and Metabolism. Cytokine. 2016; 82: 122–124. https://doi.org/10.1016/j.cyto.2015.12.019Stansberry W., Pierchala B. Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis. Front Mol Neurosci. 2023; 16: 1238453. https://doi.org/10.3389/fnmol.2023.1238453Jia C., Brown R., Malone H., et al. Ciliary Neurotrophic Factor Is a Key Sex-Specific Regulator of Depressive-Like Behavior in Mice. Psychoneuroendocrinology. 2019; 100: 96–105. https://doi.org/10.1016/j.psyneuen.2018.09.038Hayes C., Valcarcel-Ares M., Ashpole N. Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke. J Cereb Blood Flow Metab. 2021; 41(10): 2475–2491. https://doi.org/10.1177/0271678x211000894Mehrpour M., Rahatlou H., Hamzehpur N., et al. Association of insulin-like growth factor-I with the severity and outcomes of acute ischemic stroke. Iran J Neurol. 2016; 15(4): 214–218.Armbrust M., Worthmann H., Dengler R., et al. Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke. Exp Clin Endocrinol Diabetes. 2017; 125(7): 485–491. https://doi.org/10.1055/s-0043-103965Aberg N., Aberg D., Jood K., et al. Altered Levels of Circulating Insulin-Like Growth Factor I (IGF-I) Following Ischemic Stroke Are Associated with Outcome — A Prospective Observational Study. BMC Neurol. 2018; 18: 106. https://doi.org/10.1186/s12883-018-1107-3Neeraj S., Limaye L., Braighi Carvalho L., Kramer S. Effects of Aerobic Exercise on Serum Biomarkers of Neuroplasticity and Brain Repair in Stroke: A Systematic Review. Arch Phys Med Rehabil. 2021; 102(8): 1633–1644. https://doi.org/10.1016/j.apmr.2021.04.010Guo D., Zhu Z., Zhong C., et al. Increased Serum Netrin-1 Is Associated with Improved Prognosis of Ischemic Stroke: An Observational Study from CATIS. Stroke. 2019; 50(4): 845–852. https://doi.org/10.1161/strokeaha.118.024631Xu T., Zuo P., Wang Y., et al. Serum Omentin-1 Is a Novel Biomarker for Predicting the Functional Outcome of Acute Ischemic Stroke Patients. Clin Biochem. 2018; 56:350–355. https://doi.org/10.1515/cclm-2017-0282Tiedt S., Duering M., Barro C., et al. Serum Neurofilament Light: A Biomarker of Neuroaxonal Injury After Ischemic Stroke. Neurology. 2018; 91(14): e1338–e1347. https://doi.org/10.1212/wnl.0000000000006282Gao L., Xie J., Zhang H., et al. Neuron-Specific Enolase in Hypertension Patients with Acute Ischemic Stroke and Its Value Forecasting Long-Term Functional Outcomes. BMC Geriatr. 2023; 23(1): 294. https://doi.org/10.1186/s12877-023-03986-z