Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute32122610.23868/gc321226ReviewsНаучные обзорыReview ArticleGene technologies in ischemic stroke preclinical studiesГенные технологии в доклинических исследованиях ишемического инсультаhttps://orcid.org/0000-0003-4577-34486987-9144SafiullovZufar Z.СафиулловЗуфар Зуфарович
Russian Federation

MD, Cand. Sci. (Med.)

канд. мед. наук

redblackwhite@mail.ruhttps://orcid.org/0000-0002-3789-02849403-2371MarkosyanVage A.МаркосянВаге Аршалуйсович
Russian Federation
vage.markosyan@gmail.comhttps://orcid.org/0000-0002-6306-58431570-0209ChelyshevYuri A.ЧелышевЮрий Александрович
Russian Federation

MD, Dr. Sci. (Med.), Рrofessor

д-р мед. наук, профессор

chelyshev-kzn@yandex.ruKazan State Medical UniversityКазанский государственный медицинский университет310320232805202318123400903202310032023Copyright ©; 2023, Safiullov Z.Z., Markosyan V.A., Chelyshev Y.A.Copyright ©; 2023, Сафиуллов З.З., Маркосян В.А., Челышев Ю.А.2023Safiullov Z.Z., Markosyan V.A., Chelyshev Y.A.Сафиуллов З.З., Маркосян В.А., Челышев Ю.А.https://creativecommons.org/licenses/by-nc-nd/4.0/https://genescells.ru/2313-1829/article/view/321226

Ischemic stroke is one of the leading death causes and disability worldwide. The review is devoted to analysis of gene technologies application achievements in ischemic stroke experimental study.

In experimental brain ischemia, genetic constructs effectiveness studies, genes, encoding predominantly neurotrophic and angiogenic factors delivery is actively pursued. Direct gene therapy has proven its effectiveness in experimental ischemic stroke. Genetic constructs delivering methods with target genes into the ischemic brain using cellular carriers has advantages because of combined action of genes and transplanted cells. Studies on ischemic stroke models with cellular carriers overexpressing various neurotrophic and angiogenic factors confirm the safety and effectiveness of this approach, which allows us to consider transgenes cell-mediated delivery as a stroke treatment promising method.

Another significant area of gene technologies application, which is also mentioned upon in the review, is related to opto- and chemogenetic methods, which allowed obtaining new data of ischemic stroke pathogenesis cellular and molecular mechanisms.

Three main criteria were used in the review: volume of infarction, capillary density and motor activity for effectiveness comparative assessment of direct administration, transgenes number and cell-mediated delivery.

Ишемический инсульт является одной из ведущих причин смерти и инвалидности во всём мире. Настоящий обзор посвящён анализу достижений в приложении генных технологий к исследованию ишемического инсульта в эксперименте.

С использованием экспериментальной ишемии мозга продолжаются исследования эффективности применения генетических конструкций с доставкой генов, кодирующих преимущественно нейротрофические и ангиогенные факторы. Прямая генная терапия доказала свою эффективность при экспериментальном ишемическом инсульте. Способ доставки генетических конструкций с целевыми генами в ишемизированный мозг с помощью клеточных носителей имеет преимущества комбинированного действия генов и трансплантируемых клеток. Исследования на моделях ишемического инсульта с клеточными носителями, сверхэкспрессирующими различные нейротрофические и ангиогенные факторы, подтверждают безопасность и эффективность данного подхода, что позволяет рассматривать клеточно-опосредованную доставку трансгенов в качестве многообещающего способа лечения инсульта.

Другая значимая область применения генных технологий, которая также затронута в обзоре, связана с опто- и хемогенетическими методами, позволившими получить новые данные по клеточным и молекулярным механизмам патогенеза ишемического инсульта.

Проведена сравнительная оценка эффективности прямого введения ряда трансгенов и их клеточно-опосредованной доставки по трём основным критериям: объёму инфаркта, плотности капилляров и двигательной активности.

ischemic strokepenumbragene therapyoptogeneticschemogeneticsfunctional recoveryишемический инсультпенумбрагенная терапияоптогенетикахемогенетикавосстановление функцииThis work was supported by the Russian Science Foundation (grant N 19-75-10030)Научное исследование проведено при поддержке Российского научного фонда (грант № 19-75-10030)Heiss WD. Ischemic penumbra: evidence from functional imaging in man. J Cerebr Blood Flow Metab. 2000;20(9):1276–1217. doi: 10.1097/00004647-200009000-00002Heiss W.D. Ischemic penumbra: evidence from functional imaging in man // J Cerebr Blood Flow Metab. 2000. Vol. 20, N 9. P. 1276–1217. doi: 10.1097/00004647-200009000-00002Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994;36(4):557–558. doi: 10.1002/ana.410360404Hossmann K.A. Viability thresholds and the penumbra of focal ischemia // Ann Neurol. 1994. Vol. 36, N 4. P. 557–558. doi: 10.1002/ana.410360404Kornienko VN, Pronin IN. Diagnosticheskaja nejroradiologija. Vol. 1. 2008.Корниенко В.Н., Пронин И.Н. Диагностическая нейрорадиология. Т. 1. 2008.Kidwell CS, Alger JR, Saver JL. Evolving paradigms in neuroimaging of the ischemic penumbra. Stroke. 2004;35(11 suppl. 1): 2662–2665. doi: 10.1161/01.STR.0000143222.13069.70Kidwell C.S., Alger J.R., Saver J.L. Evolving paradigms in neuroimaging of the ischemic penumbra // Stroke. 2004. Vol. 35, N 11 (suppl. 1). P. 2662–2665. doi: 10.1161/01.STR.0000143222.13069.70Cristofaro B, Stone OA, Caporali A, et al. Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia. Arterioscler Thromb Vasc Biol. 2010;30(6):1143–1147. doi: 10.1161/ATVBAHA.109.205468Cristofaro B., Stone O.A., Caporali A., et al. Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia // Arterioscler Thromb Vasc Biol. 2010. Vol. 30, N 6. P. 1143–1147. doi: 10.1161/ATVBAHA.109.205468Blais M, Lévesque P, Bellenfant S, Berthod F. Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and glial-derived neurotrophic factor enhance angiogenesis in a tissue-engineered in vitro model. Tissue Eng. 2013;19(15-16):1655–1659. doi: 10.1089/ten.tea.2012.0745Blais M., Lévesque P., Bellenfant S., Berthod F. Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and glial-derived neurotrophic factor enhance angiogenesis in a tissue-engineered in vitro model // Tissue Eng. 2013. Vol. 19, N 15-16. P. 1655–1659. doi: 10.1089/ten.tea.2012.0745Zhang R, Lu Y, Li J, et al. Glial cell line-derived neurotrophic factor induced the differentiation of amniotic fluid-derived stem cells into vascular endothelial-like cells in vitro. J Mol Histol. 2016;47(1):9–19. doi: 10.1007/s10735-015-9649-9Zhang R., Lu Y., Li J., et al. Glial cell line-derived neurotrophic factor induced the differentiation of amniotic fluid-derived stem cells into vascular endothelial-like cells in vitro // J Mol Histol. 2016. Vol. 47, N 1. P. 9–19. doi: 10.1007/s10735-015-9649-9Nakamura K, Tan F, Li Z, Thiele CJ. NGF activation of TrkA induces vascular endothelial growth factor expression via induction of hypoxia-inducible factor-1α. Mol Cell Neurosci. 2011;46(2):498–506. doi: 10.1016/j.mcn.2010.12.002Nakamura K., Tan F., Li Z., Thiele C.J. NGF activation of TrkA induces vascular endothelial growth factor expression via induction of hypoxia-inducible factor-1α // Mol Cell Neurosci. 2011. Vol. 46, N 2. P. 498–506. doi: 10.1016/j.mcn.2010.12.002Wittko-Schneider IM, Schneider FT, Plate KH. Brain homeostasis: VEGF receptor 1 and 2-two unequal brothers in mind. Cell Mol Life Sci. 2013;70(10):1705–1725. doi: 10.1007/s00018-013-1279-3Wittko-Schneider I.M., Schneider F.T., Plate K.H. Brain homeostasis: VEGF receptor 1 and 2 — two unequal brothers in mind // Cell Mol Life Sci. 2013. Vol. 70, N 10. P. 1705–1725. doi: 10.1007/s00018-013-1279-3Sarkar J, Luo Y, Zhou Q, et al. VEGF receptor heterodimers and homodimers are differentially expressed in neuronal and endothelial cell types. PLoS One. 2022;17(7):e0269818. doi: 10.1371/journal.pone.0269818Sarkar J., Luo Y., Zhou Q., et al. VEGF receptor heterodimers and homodimers are differentially expressed in neuronal and endothelial cell types // PLoS One. 2022. Vol. 17, N 7. P. e0269818. doi: 10.1371/journal.pone.0269818Rosa AI, Gonsalves J, Cortes L, et al. The angiogenic factor angiopoietin-1 is a proneurogenic peptide on subventricular zone stem/progenitor cells. J Neurosci. 2010;30(13):4573–4577. doi: 10.1523/JNEUROSCI.5597-09.2010Rosa A.I., Gonsalves J., Cortes L., et al. The angiogenic factor angiopoietin-1 is a proneurogenic peptide on subventricular zone stem/progenitor cells // J Neurosci. 2010. Vol. 30, N 13. P. 4573–4577. doi: 10.1523/JNEUROSCI.5597-09.2010Luck R, Karakatsani A, Shah B, et al. The angiopoietin-Tie2 pathway regulates Purkinje cell dendritic morphogenesis in a cell-autonomous manner. Cell Rep. 2021;36(7):109522. doi: 10.1016/j.celrep.2021.109522Luck R., Karakatsani A., Shah B., et al. The angiopoietin-Tie2 pathway regulates Purkinje cell dendritic morphogenesis in a cell-autonomous manner // Cell Rep. 2021. Vol. 36, N 7. P. 109522. doi: 10.1016/j.celrep.2021.109522Chen YC, Ma NX, Pei ZF, et al. A NeuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Mol Ther. 2020;28(1):217–234. doi: 10.1016/j.ymthe.2019.09.003Chen Y.C., Ma N.X., Pei Z.F., et al. A NeuroD1 AAV-based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion // Mol Ther. 2020. Vol. 28, N 1. P. 217–234. doi: 10.1016/j.ymthe.2019.09.003Miao J, Shen LT, Tang YH, et al. Overexpression of adiponectin improves neurobehavioral outcomes after focal cerebral ischemia in aged mice. CNS Neurosci Ther. 2013;19(12):969–977. doi: 10.1111/cns.12198Miao J., Shen L.T., Tang Y.H., et al. Overexpression of adiponectin improves neurobehavioral outcomes after focal cerebral ischemia in aged mice // CNS Neurosci Ther. 2013. Vol. 19, N 12. P. 969–977. doi: 10.1111/cns.12198Meng Z, Li M, He Q, et al. Ectopic expression of human adiponectin-1 promotes functional recovery and neurogenesis after local cerebral ischemia. Neuroscience. 2014;267:135–146. doi: 10.1016/j.neuroscience.2014.02.036Meng Z., Li M., He Q., et al. Ectopic expression of human adiponectin-1 promotes functional recovery and neurogenesis after local cerebral ischemia // Neuroscience. 2014. Vol. 267. P. 135–146. doi: 10.1016/j.neuroscience.2014.02.036Duricki DA, Hutson TH, Kathe C, et al. Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke. Brain. 2016;139(Pt 1):259–275. doi: 10.1093/brain/awv341Duricki D.A., Hutson T.H., Kathe C., et al. Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke // Brain. 2016. Vol. 139(Pt 1). P. 259–275. doi: 10.1093/brain/awv341Zhang J, Li X, Chai S, Wang X. Neuroprotective effect of lentivirus mediated VEGF on rat model with cerebral ischemic injury. Int J Clin Exp Med. 2015;8(3):4094–4100.Zhang J., Li X., Chai S., Wang X. Neuroprotective effect of lentivirus mediated VEGF on rat model with cerebral ischemic injury // Int J Clin Exp Med. 2015. Vol. 8, N 3. P. 4094–4100.Shen F, Su H, Fan Y, et al. Adeno-associated viral vector-mediated hypoxia-inducible vascular endothelial growth factor gene expression attenuates ischemic brain injury after focal cerebral ischemia in mice. Stroke. 2006;37(10):2601–2606. doi: 10.1161/01.STR.0000240407.14765.e8Shen F., Su H., Fan Y., et al. Adeno-associated viral vector-mediated hypoxia-inducible vascular endothelial growth factor gene expression attenuates ischemic brain injury after focal cerebral ischemia in mice // Stroke. 2006. Vol. 37, N 10. P. 2601–2606. doi: 10.1161/01.STR.0000240407.14765.e8Shi Q, Zhanga P, Zhang J, et al. Adenovirus-mediated brain-derived neurotrophic factor expression regulated by hypoxia response element protects brain from injury of transient middle cerebral artery occlusion in mice. Neurosci Lett. 2009;465(3):220–225. doi: 10.1016/j.neulet.2009.08.049Shi Q., Zhanga P., Zhang J., et al. Adenovirus-mediated brain-derived neurotrophic factor expression regulated by hypoxia response element protects brain from injury of transient middle cerebral artery occlusion in mice // Neurosci Lett. 2009. Vol. 465, N 3. P. 220–225. doi: 10.1016/j.neulet.2009.08.049Airavaara M, Chiocco MJ, Howard DB, et al. Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury. Exp Neurol. 2010;225(1):104–113. doi: 10.1016/j.expneurol.2010.05.020Airavaara M., Chiocco M.J., Howard D.B., et al. Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury // Exp Neurol. 2010. Vol. 225, N 1. P. 104–113. doi: 10.1016/j.expneurol.2010.05.020Matlik K, Anttila JE, Kuan-Yin T, et al. Poststroke delivery of MANF promotes functional recovery in rats. Sci Adv. 2018;4(5):eaap8957. doi: 10.1126/sciadv.aap8957Matlik K., Anttila J.E., Kuan-Yin T., et al. Poststroke delivery of MANF promotes functional recovery in rats // Sci Adv. 2018. Vol. 4, N 5. P. eaap8957. doi: 10.1126/sciadv.aap8957Liu Y, Long L, Zhang F, et al. Microneedle-mediated vascular endothelial growth factor delivery promotes angiogenesis and functional recovery after stroke. J Control Release. 2021;338:610–622. doi: 10.1016/j.jconrel.2021.08.057Liu Y., Long L., Zhang F., et al. Microneedle-mediated vascular endothelial growth factor delivery promotes angiogenesis and functional recovery after stroke // J Control Release. 2021. Vol. 338. P. 610–622. doi: 10.1016/j.jconrel.2021.08.057Shen F, Walker EJ, Jiang L, et al. Coexpression of angiopoietin-1 with VEGF increases the structural integrity of the blood-brain barrier and reduces atrophy volume. J Cereb Blood Flow Metab. 2011;31(12):2343–2351. doi: 10.1038/jcbfm.2011.97Shen F., Walker E.J., Jiang L., et al. Coexpression of angiopoietin-1 with VEGF increases the structural integrity of the blood-brain barrier and reduces atrophy volume // J Cereb Blood Flow Metab. 2011. Vol. 31, N 12. P. 2343–2351. doi: 10.1038/jcbfm.2011.97Sun H, Le T, Chang TT, et al. AAV-mediated Netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke. Neurobiol Dis. 2011;44(1):73–83. doi: 10.1016/j.nbd.2011.06.006Sun H., Le T., Chang T.T., et al. AAV-mediated Netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke // Neurobiol Dis. 2011. Vol. 44, N 1. P. 73–83. doi: 10.1016/j.nbd.2011.06.006Shimamura M, Sato N, Oshima K, et al. Novel therapeutic strategy to treat brain ischemia overexpression of hepatocyte growth factor gene reduced ischemic injury without cerebral edema in rat model. Circulation. 2004;109(3):424–431. doi: 10.1161/01.CIR.0000109496.82683.49Shimamura M., Sato N., Oshima K., et al. Novel therapeutic strategy to treat brain ischemia overexpression of hepatocyte growth factor gene reduced ischemic injury without cerebral edema in rat model // Circulation. 2004. Vol. 109, N 3. P. 424–431. doi: 10.1161/01.CIR.0000109496.82683.49Shirakura M, Inoue M, Fujikawa S, et al. Postischemic administration of Sendai virus vector carrying neurotrophic factor genes prevents delayed neuronal death in gerbils. Gene Ther. 2004;11(9):784–790. doi: 10.1038/sj.gt.3302224Shirakura M., Inoue M., Fujikawa S., et al. Postischemic administration of Sendai virus vector carrying neurotrophic factor genes prevents delayed neuronal death in gerbils // Gene Ther. 2004. Vol. 11, N 9. P. 784–790. doi: 10.1038/sj.gt.3302224Hermann DM, Kilic E, Kügler S, et al. Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiol Dis. 2001;8(4):655–666. doi: 10.1006/nbdi.2001.0399Hermann D.M., Kilic E., Kügler S., et al. Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice // Neurobiol Dis. 2001. Vol. 8, N 4. P. 655–666. doi: 10.1006/nbdi.2001.0399Shirakura M, Fukumura M, Inoue M, et al. Sendai virus vector-mediated gene transfer of glial cell line-derived neurotrophic factor prevents delayed neuronal death after transient global ischemia in gerbils. Exp Anim. 2003;52(2):119–127. doi: 10.1538/expanim.52.119Shirakura M., Fukumura M., Inoue M., et al. Sendai virus vector-mediated gene transfer of glial cell line-derived neurotrophic factor prevents delayed neuronal death after transient global ischemia in gerbils // Exp Anim. 2003. Vol. 52, N 2. P. 119–127. doi: 10.1538/expanim.52.119Yoo J, Seo JJ, Eom JH, et al. Effects of stromal cell-derived factor 1 delivered at different phases of transient focal ischemia in rats. Neuroscience. 2012;209:171–186. doi: 10.1016/j.neuroscience.2012.02.031Yoo J., Seo J.J., Eom J.H., et al. Effects of stromal cell-derived factor 1 delivered at different phases of transient focal ischemia in rats // Neuroscience. 2012. Vol. 209. P. 171–186. doi: 10.1016/j.neuroscience.2012.02.031Zhang J, Yu Z, Yu Z, et al. rAAV-mediated delivery of brain-derived neurotrophic factor promotes neurite outgrowth and protects neurodegeneration in focal ischemic model. Int J Clin Exp Pathol. 2011;4(5):496–504.Zhang J., Yu Z., Yu Z., et al. rAAV-mediated delivery of brain-derived neurotrophic factor promotes neurite outgrowth and protects neurodegeneration in focal ischemic model // Int J Clin Exp Pathol. 2011. Vol. 4, N 5. P. 496–504.Beker M, Caglayand AB, Beker MC, et al. Lentivirally administered glial cell line-derived neurotrophic factor promotes post-ischemic neurological recovery, brain remodeling and contralesional pyramidal tract plasticity by regulating axonal growth inhibitors and guidance proteins. Exp Neurol. 2020;331:113364. doi: 10.1016/j.expneurol.2020.113364Beker M., Caglayand A.B., Beker M.C., et al. Lentivirally administered glial cell line-derived neurotrophic factor promotes post-ischemic neurological recovery, brain remodeling and contralesional pyramidal tract plasticity by regulating axonal growth inhibitors and guidance proteins. Exp Neurol. 2020. Vol. 331. P. 113364. doi: 10.1016/j.expneurol.2020.113364Andsberg G, Kokaia Z, Klein RL, et al. Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats. Neurobiol Dis. 2002;9(2):187–204. doi: 10.1006/nbdi.2001.0456Andsberg G., Kokaia Z., Klein R.L., et al. Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats // Neurobiol Dis. 2002. Vol. 9, N 2. P. 187–204. doi: 10.1006/nbdi.2001.0456He X, Li Y, Lu H, et al. Netrin-1 overexpression promotes white matter repairing and remodeling after focal cerebral ischemia in mic. J Cereb Blood Flow Metab. 2013;33(12):1921–1927. doi: 10.1038/jcbfm.2013.150He X., Li Y., Lu H., et al. Netrin-1 overexpression promotes white matter repairing and remodeling after focal cerebral ischemia in mic // J Cereb Blood Flow Metab. 2013. Vol. 33, N 12. P. 1921–1927. doi: 10.1038/jcbfm.2013.150Zheng M, Chen R, Chen H, et al. Netrin-1 promotes synaptic formation and axonal regeneration via JNK1/c-Jun pathway after the middle cerebral artery occlusion. Front Cell Neurosci. 2018;12:13. doi: 10.3389/fncel.2018.00013Zheng M., Chen R., Chen H., et al. Netrin-1 promotes synaptic formation and axonal regeneration via JNK1/c-Jun pathway after the middle cerebral artery occlusion // Front Cell Neurosci. 2018. Vol. 12. P. 13. doi: 10.3389/fncel.2018.00013Zhu W, Fan Y, Frenzel T, et al. Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice. Stroke. 2008;39(4):1254–1261. doi: 10.1161/STROKEAHA.107.500801Zhu W., Fan Y., Frenzel T., et al. Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice // Stroke. 2008. Vol. 39, N 4. P. 1254–1261. doi: 10.1161/STROKEAHA.107.500801Yu SJ, Tseng KY, Shen H, et al. Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats. PLoS One. 2013;8(12):e81750. doi: 10.1371/journal.pone.0081750Yu S.J., Tseng K.Y., Shen H., et al. Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats // PLoS One. 2013. Vol. 8, N 12. P. e81750. doi: 10.1371/journal.pone.0081750Harvey BK, Chang CF, Chiang YH, et al. HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. Exp Neurol. 2003;183(1):47–55. doi: 10.1016/s0014-4886(03)00080-3Harvey B.K., Chang C.F., Chiang Y.H., et al. HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury // Exp Neurol. 2003. Vol. 183, N 1. P. 47–55. doi: 10.1016/s0014-4886(03)00080-3Hu GJ, Feng YG, Lu WP, et al. Effect of combined VEGF165/SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia. J Neurosurg. 2017;127(3):670–678. doi: 10.3171/2016.9.JNS161234Hu G.J., Feng Y.G., Lu W.P., et al. Effect of combined VEGF165/SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia // J Neurosurg. 2017. Vol. 127, N 3. P. 670–678. doi: 10.3171/2016.9.JNS161234Li SF, Meng QH, Yao WC, et al. Recombinant AAV1 mediated vascular endothelial growth factor gene expression promotes angiogenesis and improves neural function: experiment with rats. Zhonghua Yi Xue Za Zhi. 2009;89(3):167–170.Li S.F., Meng Q.H., Yao W.C., et al. Recombinant AAV1 mediated vascular endothelial growth factor gene expression promotes angiogenesis and improves neural function: experiment with rats // Zhonghua Yi Xue Za Zhi. 2009. Vol. 89, N 3. P. 167–170.Sokolov ME, Bashirov FV, Markosyan VA, et al. Triple-gene therapy for stroke: a proof-of-concept in vivo study in rats. Front Pharmacol. 2018;9:111. doi: 10.3389/fphar.2018.00111Sokolov M.E., Bashirov F.V., Markosyan V.A., et al. Triple-gene therapy for stroke: a proof-of-concept in vivo study in rats // Front Pharmacol. 2018. Vol. 9. P. 111. doi: 10.3389/fphar.2018.00111Lu H, Liu X, Zhang N, et al. Neuroprotective effects of brain-derived neurotrophic factor and noggin-modified bone mesenchymal stem cells in focal cerebral ischemia in rats. J Stroke Cerebrovasc Dis. 2016;25(2):410–418. doi: 10.1016/j.jstrokecerebrovasdis.2015.10.013Lu H., Liu X., Zhang N., et al. Neuroprotective effects of brain-derived neurotrophic factor and noggin-modified bone mesenchymal stem cells in focal cerebral ischemia in rats // J Stroke Cerebrovasc Dis. 2016. Vol. 25, N 2. P. 410–418. doi: 10.1016/j.jstrokecerebrovasdis.2015.10.013Zhang Q, Zhou M, Wu X, et al. Promoting therapeutic angiogenesis of focal cerebral ischemia using thrombospondin-4 (TSP4) gene-modified bone marrow stromal cells (BMSCs) in a rat model. J Transl Med. 2019;17(1):111. doi: 10.1186/s12967-019-1845-zZhang Q., Zhou M., Wu X., et al. Promoting therapeutic angiogenesis of focal cerebral ischemia using thrombospondin-4 (TSP4) gene-modified bone marrow stromal cells (BMSCs) in a rat model // J Transl Med. 2019. Vol. 17, N 1. P. 111. doi: 10.1186/s12967-019-1845-zSun S, Gao N, Hu X, et al. SOD3 overexpression alleviates cerebral ischemia-reperfusion injury in rats. Mol Genet Genomic Med. 2019;7(10):e00831. doi: 10.1002/mgg3.831Sun S., Gao N., Hu X., et al. SOD3 overexpression alleviates cerebral ischemia-reperfusion injury in rats // Mol Genet Genomic Med. 2019. Vol. 7, N 10. P. e00831. doi: 10.1002/mgg3.831Safiullov ZZ, Izmailov AA, Sokolov ME, et al. Autologous genetically enriched leucoconcentrate in the preventive and acute phases of stroke treatment in a mini-pig model. Pharmaceutics. 2022;14(10):2209. doi: 10.3390/pharmaceutics14102209Safiullov Z.Z., Izmailov A.A., Sokolov M.E., et al. Autologous genetically enriched leucoconcentrate in the preventive and acute phases of stroke treatment in a mini-pig model // Pharmaceutics. 2022. Vol. 14, N 10. P. 2209. doi: 10.3390/pharmaceutics14102209Wang F, Tang H, Zhu J, Zhang JH. Transplanting mesenchymal stem cells for treatment of ischemic stroke. Cell Transplant. 2018;27(12):1825–1834. doi: 10.1177/0963689718795424Wang F., Tang H., Zhu J., Zhang J.H. Transplanting mesenchymal stem cells for treatment of ischemic stroke // Cell Transplant. 2018. Vol. 27, N 12. P. 1825–1834. doi: 10.1177/0963689718795424Yang Y, Hu X, Qin Q, et al. Optimal therapeutic conditions for the neural stem cell-based management of ischemic stroke: a systematic review and network meta-analysis based on animal studies. BMC Neurol. 2022;22(1):345. doi: 10.1186/s12883-022-02875-zYang Y., Hu X., Qin Q., et al. Optimal therapeutic conditions for the neural stem cell-based management of ischemic stroke: a systematic review and network meta-analysis based on animal studies // BMC Neurol. 2022. Vol. 22, N 1. P. 345. doi: 10.1186/s12883-022-02875-zKurozumi K, Nakamura K, Tamiya T. Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther. 2005;11(1):96–104. doi: 10.1016/j.ymthe.2004.09.020Kurozumi K., Nakamura K., Tamiya T. Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model // Mol Ther. 2005. Vol. 11, N 1. P. 96–104. doi: 10.1016/j.ymthe.2004.09.020Ding J, Cheng Y, Gao S, Chen J. Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res. 2011;89(2):222–230. doi: 10.1002/jnr.22535Ding J., Cheng Y., Gao S., Chen J. Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats // J Neurosci Res. 2011. Vol. 89, N 2. P. 222–230. doi: 10.1002/jnr.22535Marushima A, Nieminen M, Kremenetskaia I, et al. Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia. J Cereb Blood Flow Metab. 2020;40(2):404–419. doi: 10.1177/0271678X18818298Marushima A., Nieminen M., Kremenetskaia I., et al. Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia // J Cereb Blood Flow Metab. 2020. Vol. 40, N 2. P. 404–419. doi: 10.1177/0271678X18818298Markosyan V, Safiullov Z, Izmailov A, et al. Preventive triple gene therapy reduces the negative consequences of ischemia-induced brain injury after modelling stroke in a rat. Int J Mol Sci. 2020;21(18):6858. doi: 10.3390/ijms21186858Markosyan V., Safiullov Z., Izmailov A., et al. Preventive triple gene therapy reduces the negative consequences of ischemia-induced brain injury after modelling stroke in a rat // Int J Mol Sci. 2020. Vol. 21, N 18. P. 6858. doi: 10.3390/ijms21186858Onda T, Honmou O, Harada K, et al. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab. 2008;28(2):329–340. doi: 10.1038/sj.jcbfm.9600527Onda T., Honmou O., Harada K., et al. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia // J Cereb Blood Flow Metab. 2008. Vol. 28, N 2. P. 329–340. doi: 10.1038/sj.jcbfm.9600527Toyama K, Honmou O, Harada K, et al. Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia. Exp Neurol. 2009;216(1):47–55. doi: 10.1016/j.expneurol.2008.11.010Toyama K., Honmou O., Harada K., et al. Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia // Exp Neurol. 2009. Vol. 216, N 1. P. 47–55. doi: 10.1016/j.expneurol.2008.11.010Wu W, Chen X, Hu C, et al. Transplantation of neural stem cells expressing hypoxiainducible factor-1α (HIF-1α) improves behavioral recovery in a rat stroke model. J Clin Neurosci. 2010;17(1):92–95. doi: 10.1016/j.jocn.2009.03.039Wu W., Chen X., Hu C., et al. Transplantation of neural stem cells expressing hypoxiainducible factor-1α (HIF-1α) improves behavioral recovery in a rat stroke model // J Clin Neurosci. 2010. Vol. 17, N 1. P. 92–95. doi: 10.1016/j.jocn.2009.03.039Yang C, Liu H, Liu D. Mutant hypoxia–inducible factor 1α modified bone marrow mesenchymal stem cells ameliorate cerebral ischemia. Int J Mol Med. 2014;34(6):1622–1628. doi: 10.3892/ijmm.2014.1953Yang C., Liu H., Liu D. Mutant hypoxia–inducible factor 1α modified bone marrow mesenchymal stem cells ameliorate cerebral ischemia // Int J Mol Med. 2014;34(6):1622–1628. doi: 10.3892/ijmm.2014.1953Ye ZZ, Ye WB, Deng YB, et al. HIF-1-modified BMSCs improve migration and reduce neuronal apoptosis after stroke in rats. Chin Sci Bull. 2013;58:3519–3528. doi: 10.1007/s11434-013-5936-6Ye Z.Z., Ye W.B., Deng Y.B., et al. HIF-1-modified BMSCs improve migration and reduce neuronal apoptosis after stroke in rats // Chin Sci Bull. 2013. Vol. 58. P. 3519–3528. doi: 10.1007/s11434-013-5936-6Liu H, Honmou O, Harada K, et al. Neuroprotection by PlGF gene modified human mesenchymal stem cells after cerebral ischaemia. Brain. 2006;129(Pt 10):2734–2745. doi: 10.1093/brain/awl207Liu H., Honmou O., Harada K., et al. Neuroprotection by PlGF gene modified human mesenchymal stem cells after cerebral ischaemia // Brain. 2006. Vol. 129(Pt 10). P. 2734–2745. doi: 10.1093/brain/awl207Nomura T, Honmou O, Harada K, et al. IV infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience. 2005;136(1):161–169. doi: 10.1016/j.neuroscience.2005.06.062Nomura T., Honmou O., Harada K., et al. IV infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat // Neuroscience. 2005. Vol. 136, N 1. P. 161–169. doi: 10.1016/j.neuroscience.2005.06.062Miki Y, Nonoguchi N, Ikeda N, et al. Vascular endothelial growth factor genetransferred bone marrow stromal cells engineered with a herpes simplex virus type 1 vector can improve neurological deficits and reduce infarction volume in rat brain ischemia. Neurosurgery. 2007;61(3):586–594. doi: 10.1227/01.NEU.0000290907.30814.42Miki Y., Nonoguchi N., Ikeda N., et al. Vascular endothelial growth factor genetransferred bone marrow stromal cells engineered with a herpes simplex virus type 1 vector can improve neurological deficits and reduce infarction volume in rat brain ischemia // Neurosurgery. 2007. Vol. 61, N 3. P. 586–594. doi: 10.1227/01.NEU.0000290907.30814.42Horita Y, Honmou O, Harada K, et al. Intravenous administration of glial cell line derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. J Neurosci Res. 2006;84(7):1495–1504. doi: 10.1002/jnr.21056Horita Y., Honmou O., Harada K., et al. Intravenous administration of glial cell line derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat // J Neurosci Res. 2006. Vol. 84, N 7. P. 1495–1504. doi: 10.1002/jnr.21056Lu C, Wu X, Ma H, et al. Optogenetic stimulation enhanced neuronal plasticities in motor recovery after ischemic stroke. Neural Plast. 2019;2019:5271573. doi: 10.1155/2019/5271573Lu C., Wu X., Ma H., et al. Optogenetic stimulation enhanced neuronal plasticities in motor recovery after ischemic stroke // Neural Plast. 2019. Vol. 2019. P. 5271573. doi: 10.1155/2019/5271573Cheng MY, Wang EH, Steinberg GK. Optogenetic approaches to study stroke recovery. ACS Chem Neurosci. 2014;5(12):1144–1145. doi: 10.1021/cn500216fCheng M.Y., Wang E.H., Steinberg G.K. Optogenetic approaches to study stroke recovery // ACS Chem Neurosci. 2014. Vol. 5, N 12. P. 1144–1145. doi: 10.1021/cn500216fAzad TD, Veeravagu A, Steinberg GK. Neurorestoration after stroke. Neurosurg Focus. 2016;40(5):E2. doi: 10.3171/2016.2.FOCUS15637Azad T.D., Veeravagu A., Steinberg G.K. Neurorestoration after stroke // Neurosurg Focus. 2016. Vol. 40, N 5. P. E2. doi: 10.3171/2016.2.FOCUS15637Anenberg E, Arstikaitis P, Niitsu Y, et al. Ministrokes in channelrhodopsin-2 transgenic mice reveal widespread deficits in motor output despite maintenance of cortical neuronal excitability. J Neurosci. 2014;34(4):1094–1104. doi: 10.1523/JNEUROSCI.1442-13.2014Anenberg E., Arstikaitis P., Niitsu Y., et al. Ministrokes in channelrhodopsin-2 transgenic mice reveal widespread deficits in motor output despite maintenance of cortical neuronal excitability // J Neurosci. 2014. Vol. 34, N 4. P. 1094–1104. doi: 10.1523/JNEUROSCI.1442-13.2014Bo B, Li Y, Li W, et al. Neurovascular coupling impairment in acute ischemic stroke by optogenetics and optical brain imaging. Ann Int Conf IEEE Eng Med Biol Soc. 2020;2020:3727–3730. doi: 10.1109/EMBC44109.2020.9176641Bo B., Li Y., Li W., et al. Neurovascular coupling impairment in acute ischemic stroke by optogenetics and optical brain imaging // Ann Int Conf IEEE Eng Med Biol Soc. 2020. Vol. 2020. P. 3727–3730. doi: 10.1109/EMBC44109.2020.9176641Jiang L, Li W, Mamtilahun M, et al. Optogenetic inhibition of striatal GABAergic neuronal activity improves outcomes after ischemic brain injury. Stroke. 2017;48(12):3375–3383. doi: 10.1161/STROKEAHA.117.019017Jiang L., Li W., Mamtilahun M., et al. Optogenetic inhibition of striatal GABAergic neuronal activity improves outcomes after ischemic brain injury // Stroke. 2017. Vol. 48, N 12. P. 3375–3383. doi: 10.1161/STROKEAHA.117.019017Cheng MY, Wang EH, Woodson WJ, et al. Optogenetic neuronal stimulation promotes functional recovery after stroke. Proc Natl Acad Sci USA. 2014;111(35):12913–12918. doi: 10.1073/pnas.1404109111Cheng M.Y., Wang E.H., Woodson W.J., et al. Optogenetic neuronal stimulation promotes functional recovery after stroke // Proc Natl Acad Sci USA. 2014. Vol. 111, N 35. P. 12913–12918. doi: 10.1073/pnas.1404109111Daadi MM, Klausner JQ, Bajar B, et al. Optogenetic stimulation of neural grafts enhances neurotransmission and downregulates the inflammatory response in experimental stroke model. Cell Transplant. 2016;25(7):1371–1380. doi: 10.3727/096368915X688533Daadi M.M., Klausner J.Q., Bajar B., et al. Optogenetic stimulation of neural grafts enhances neurotransmission and downregulates the inflammatory response in experimental stroke model // Cell Transplant. 2016. Vol. 25, N 7. P. 1371–1380. doi: 10.3727/096368915X688533Yu SP, Tung JK, Wei ZZ, et al. Optochemogenetic stimulation of transplanted iPS-NPCs enhances neuronal repair and functional recovery after ischemic stroke. J Neurosci. 2019;39(33):6571–6594. doi: 10.1523/JNEUROSCI.2010-18.2019Yu S.P., Tung J.K., Wei Z.Z., et al. Optochemogenetic stimulation of transplanted iPS-NPCs enhances neuronal repair and functional recovery after ischemic stroke // J Neurosci. 2019. Vol. 39, N 33. P. 6571–6594. doi: 10.1523/JNEUROSCI.2010-18.2019Wang YC, Galeffi F, Wang W, et al. Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome. Exp Neurol. 2020;326:113206. doi: 10.1016/j.expneurol.2020.113206Wang Y.C., Galeffi F., Wang W., et al. Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome // Exp Neurol. 2020. Vol. 326. P. 113206. doi: 10.1016/j.expneurol.2020.113206Hu KH, Li YA, Jia W, et al. Chemogenetic activation of glutamatergic neurons in the motor cortex promotes functional recovery after ischemic stroke in rats. Behav Brain Res. 2019;359:81–88. doi: 10.1016/j.bbr.2018.10.029Hu K.H., Li Y.A., Jia W., et al. Chemogenetic activation of glutamatergic neurons in the motor cortex promotes functional recovery after ischemic stroke in rats // Behav Brain Res. 2019. Vol. 359. P. 81–88. doi: 10.1016/j.bbr.2018.10.029Caracciolo L, Marosi M, Mazzitelli J, et al. CREB controls cortical circuit plasticity and functional recovery after stroke. Nat Commun. 2018;9(1):2250. doi: 10.1038/s41467-018-04445-9Caracciolo L., Marosi M., Mazzitelli J., et al. CREB controls cortical circuit plasticity and functional recovery after stroke // Nat Commun. 2018. Vol. 9, N 1. P. 2250. doi: 10.1038/s41467-018-04445-9