Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC10410.15690/vramn.v68i12.856РATHOPHYSIOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ПАТОФИЗИОЛОГИИCURRENT CONCEPTS OF PERINATAL ISCHEMIC INJURY IN THE BRAIN NEUROVASCULAR UNIT: MOLECULAR TARGETS FOR NEUROPROTECTIONСОВРЕМЕННЫЕ ПРЕДСТАВЛЕНИЯ О ПАТОГЕНЕЗЕ ПЕРИНАТАЛЬНОГО ИШЕМИЧЕСКОГО ПОВРЕЖДЕНИЯ КЛЕТОК НЕЙРОВАСКУЛЯРНОЙ ЕДИНИЦЫ ГОЛОВНОГО МОЗГА: МОЛЕКУЛЫ-МИШЕНИ ДЛЯ НЕЙРОПРОТЕКЦИИMorgunA. V.МоргунА. В.
Russian Federation

MD, assistant of Pediatric Department of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 243-39-52

441682@mail.ruKuvachevaN. V.КувачеваН. В.
Russian Federation

MD, associate professor of the Department of Biological Chemistry with the Course of Medical, Pharmaceutical and Toxicological Chemistry of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

natalya.kuvacheva@gmail.comTaranushenkoT. E.ТаранушенкоТ. Е.
Russian Federation

PhD, professor, Head of Pediatric Department of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 243-39-52

tetar@mail.ruKhilazhievaE. D.ХилажеваЕ. Д.
Russian Federation

assistant of the Department of Biological Chemistry with the Course of Medical, Pharmaceutical and Toxicological Chemistry of Krasnoyarsk State Medical University Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

elena.hilazheva@mail.ruMalinovskayaN. A.МалиновскаяН. А.
Russian Federation

MD, research scientist of Research Institute of Molecular Medicine and Pathobiochemistry of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

konsuelo81@mail.ruGorinaYa. V.ГоринаЯ. В.
Russian Federation

MD, senior lecturer of the Department of Biological Chemistry with the Course of Medical, Pharmaceutical and Toxicological Chemistry of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

yana_20@bk.ruPozhilenkovaE. A.ПожиленковаЕ. А.
Russian Federation

MD, associate professor of the Department of Biological Chemistry with the Course of Medical, Pharmaceutical and Toxicological Chemistry of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

pozhilenkova@yandex.ruFrolovaO. V.ФроловаО. Ф.
Russian Federation

research scientist of Research Institute of Molecular Medicine and Pathobiochemistry of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

frolova_olga86@mail.ruSalminaA. B.СалминаА. Б.
Russian Federation

PhD, professor, Head of the Department of Biological Chemistry with the Course of Medical, Pharmaceutical and Toxicological Chemistry of Krasnoyarsk State Medical University. Address: 1, P. Zheleznyak Street, Krasnoyarsk, RF, 660022; tel.: +7 (391) 228-07-69

allasalmina@mail.ruKrasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky, Russian FederationКрасноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого, Российская Федерация101220136812Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук263507082015Copyright ©; 1970, "Paediatrician" Publishers LLCCopyright ©; 1970, Издательство "Педиатръ"1970"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/104

Perinatal hypoxic-ischemic brain injury is a relevant medical and social problem. Among many pathological processes in the neonatal period perinatal hypoxic-ischemic injury is a major cause of further hemorrhage, necrotic and atrophic changes in the brain. This review presents recent data on the basic mechanisms of the hypoxic-ischemic brain injury along the concept of neurovascular unit (neurons, astrocytes, endothelial cells, pericytes) with the focus on alterations in cell-to-cell communication. Pathological changes caused by ischemia-hypoxia are considered within two phases of injury (ischemic phase and reperfusion phase). The review highlights changes in each individual component of the neurovascular unit and their interactions. Molecular targets for pharmacological improvement of intercellular communication within neurovascular unit as a therapeutic strategy in perinatal brain injury are discussed.

Гипоксически-ишемическое поражение головного мозга новорожденного ребенка остается актуальной медицинской и социальной проблемой. Среди множества патологических процессов у новорожденных перинатальные гипоксически-ишемические поражения сами по себе являются основным патогенетическим звеном последующих кровоизлияний, некротических и атрофических изменений головного мозга. В обзоре представлены современные данные об основных механизмах повреждающего гипоксически-ишемического действия на клетки-компоненты нейроваскулярной единицы (нейроны, астроциты, эндотелиоциты, перициты), а также возникающих при этом нарушениях межклеточных взаимодействий. Патологические изменения, развивающиеся в результате гипоксии-ишемии, описаны с учетом наличия двух фаз повреждения (фаза ишемии и фаза реперфузии) и освещаются индивидуальные изменения каждого компонента нейроваскулярной единицы и их взаимодействий. Рассматриваются основные направления фармакологического воздействия на клеточно-молекулярные и патобиохимические механизмы перинатального гипоксически-ишемического повреждения головного мозга.

neurovascular unitintercellular communicationsperinatal hypoxic-ischemic brain injuryнейроваскулярная единицамежклеточные взаимодействияперинатальное гипоксически-ишемическое повреждение головного мозга1. Gulamova S.R., Alieva S.A., Nagieva Kh.M., Bagirova A.G. Svit meditsini ta biologii = Light of medicine and biology. 2011; 7(3): 55–58.2. Kapranova E.I., Belousova N.A. Doktor.ru = Doktor.ru. 2012; 9: 40–43.3. Yanushanets N.Yu. Ros. vestn. perinatologii i pediatrii = Russian bulletin of perinatology and pediatrics. 2006; 51(4): 53–55.4. Pal'chik A.B., Shabalov N.P. Gipoksicheski-ishemicheskaya entsefalopatiya novorozhdennykh: Rukovodstvo dlya vrachei [Hypoxic-ischemic Encephalopathy of Newborns: Guideline for Doctors]. St.-Petersburg, Piter, 2006. 224 p.5. Mikhalev E.V., Krivonogova T.S., Tropova T.E., Bybchenko E.G., Zhelev V.A. Mat' i ditya v Kuzbasse – Mother and child in Kuzbass. 2011; 4: 40–42.6. Platt M.J., Cans C., Johnson A., Surman G., Topp M., Torrioli M.G., Krageloh-Mann I. Trends in cerebral palsy among infants of very low birthweigth (< 1500 g) or born prematurely (< 32 weeks) in 16 European centers: A database study. Lancet. 2007; 369: 43-50.7. Baburamani A.A., Ek C.J., Walker D.W., Castillo-Melendez M. Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair? Front. Physiol. 2012; 3: 424.8. Vlasyuk V.V. Rodovaya travma i perinatal'nye narusheniya mozgovogo krovoobrashcheniya [Birth Injury and Perinatal Disorders of Cerebral Blood Flow].St.-Petersburg, Nestor-Istoriya, 2009. 252 p.9. Barashnev Yu.I., Rozanov A.V., Panov V.O., Volobuev A.I. Ros. vestn. perinatologii i pediatrii = Russian bulletin of perinatology and pediatrics. 2006; 51(4): 41–46.10. Volpe J.J. The encephalopathy of prematurity – brain injury and impaired brain development inextricably intertwined. Semin. Pediatr. Neurol. 2009; 16 (4): 167-178.11. Medvedev M.I., Degtyareva M.G., Gorbunov A.V., Grebennikova O.V., Dulenkov A.B., Voronov V.V. Pediatriya = Pediatrics. 2011; 90(1): 66–70.12. Barashnev Yu.I. Perinatal'naya nevrologiya [Perinatal Neurology]. Moscow, Triada-X. 2011. 670 p.13. Salmina A.B., Fursov A.A., Mikhutkina S.V., Morgun A.V., Zykova L.D., Musaeva O.F., Fursov M.A., Laletin D.I., Yudin G.V., Trufanova L.V., Shnaider N.A. Sibirskoe meditsinskoe obozrenie = Siberian medical review. 2006; 41(4): 22–27.14. Barkovich A.J. Magnetic resonance techniques in the assessment of myelin and myelination. J. Inherit. Metab. Dis. 2005; 28: 311-343.15. Ballabh P., Braun A., Nedergaard M. The blood-brain barrier an overview: structure, regulation, and clinical implications. Neurobiol. Dis. 2004; 16: 1-13.16. Kuvacheva N.V., Salmina A.B., Komleva Yu.K., Malinovskaya N.A., Morgun A.V., Pozhilenkova E.A., Zamai G.S., Yauzina N.A., Petrova M.M. Zhurnal nevrologii i psikhiatrii im. C.C. Korsakova = S.S. Korsakov Journal of neurology and psychiatry. 2013; 113(4): 80–85.17. Fan X., Kavelaars A., Heijnen C.J., Groenendaal F., van Bel F. Pharmacological neuroprotection after perinatal hypoxic-ischemic brain injury. Curr. Neuropharmacol. 2010; 8 (4): 324-334.18. Iang I., Rozenberg G.A. Stroke. Rossiiskoe izdanie = Stroke. Russian publication. 2012; 1: 91–96.19. Salmina A.B., Okuneva O.S., Taranushenko T.E., Fursov A.A., Prokopenko S.V., Mikhutkina S.V., Malinovskaya N.A., Tagaeva G.A. Annaly klinicheskoi i eksperimental'noi nevrologii = Annals of clinical and experimental neurology. 2008; 2(3): 44–51.20. Liang J., Takeuchi H., Doi Y., Kawanokuchi J., Sonobe Y., Jin S., Yawata I., Li H., Yasuoka S., Mizuno T., Suzumura A. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res. 2008; 1210: 11-19.21. Uwechue N.M., Marx M.C., Chevy Q., Billups B. Activation of glutamate transport evokes rapid glutamine release from perisynaptic astrocytes. J Physiol. 2012; 590 (Pt 10): 2317-2331.22. Weilinger N.L., Tang P.L., Thompson R.J. J. Neurosci. 2012; 32 (36): 12579-12588.23. Giaume C., Koulakoff A., Roux L., Holcman D., Rouach N. Nat. Rev. Neurosci. 2010; 11 (2): 87-99.24. Iglesias R.M., Spray D.C. Neurochem. Res. 2012; 37 (6): 1355-1363.25. Heinrich A., Andó R.D., Túri G., Rózsa B., Sperlágh B. Brit. J. Pharmacol. 2012; 167 (5): 1003-1020.26. Minkiewicz J., de Rivero Vaccari J.P., Keane R.W. Glia. 2013; 61 (7): 1113-1121.27. Bennett M.V., Garré J.M., Orellana J.A., Bukauskas F.F., Nedergaard M., Sáez J.C. Brain Res. 2012; 1487: 3-15.28. Cone A.C., Ambrosi C., Scemes E., Martone M.E., Sosinsky G.E. Front. Pharmacol. 2013; 4: 6.29. Franke H., Günther A., Grosche J., Schmidt R., Rossner S., Reinhardt R., Faber-Zuschratter H., Schneider D., Illes P. J. Neuropathol. Exp. Neurol. 2004; 63 (7): 686-699.30. Lai Р.С., Huang Y.T., Wu C.C., Lai C.J., Wang P.J., Chiu T.H. Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats. J. Biomed. Sci. 2011; 18 (1): 69.31. Leibowitz A., Boyko M., Shapira Y., Zlotnik A. Blood glutamate scavenging: insight into neuroprotection. Int. J. Mol. Sci. 2012; 13 (8): 10041-10066.32. Distefano G., Praticò A.D. Actualities on molecular pathogenesis and repairing processes of cerebral damage in perinatal hypoxic-ischemic encephalopathy. Ital. J. Pediatr. 2010; 36: 63.33. Papazisis G., Pourzitaki C., Sardeli C., Lallas A., Amaniti E., Kouvelas D. Deferoxamine decreases the excitatory amino acid levels and improves the histological outcome in the hippocampus of neonatal rats after hypoxia-ischemia. Pharmacol. Res. 2008; 57 (1): 73-78.34. Cimino M., Balduini W., Carloni S., Gelosa P., Guerrini U., Tremoli E., Sironi L. Neuroprotective effect of simvastatin in stroke: a comparison between adult and neonatal rat models of cerebral ischemia. Neurotoxicology. 2005; 26 (5): 929-933.35. Fabian R.H., Perez-Polo J.R., Kent T.A. Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia. Am. J. Physiol. Heart. Circ. Physiol. 2008; 295 (4): 1809-1814.36. Loginova I.G., Afonin A.A., Drukker N.A. Sovremennye problemy nauki i obrazovaniya. 2013; 2: 21–29.37. Chekeni F.B., Elliott M.R., Sandilos J.K., Walk S.F., Kinchen J.M., Lazarowski E.R., Armstrong A.J., Penuela S., Laird D.W., Salvesen G.S., Isakson B.E., Bayliss D.A, Ravichandran KS. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature. 2010; 14 (467): 863-867.38. Bargiotas P., Krenz A., Monyer H., Schwaninger M. Channels (Austin). 2012; 6 (6): 453-456.39. Leonardo C.C., Pennypacker K.R. Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J. Neuroinflamm. 2009; 6: 13.40. Morgun A.V., Ovcharenko N.V., Taranushenko T.E., Ustinova S.I., Okuneva O.S., Antonova S.K., Gilyazova D.F., Uspenskaya O.A., Salmina A.B. Sibirskoe meditsinskoe obozrenie = Siberian medical review. 2013; 3: 3–10.41. Jellema R.K., Lima Passos V., Zwanenburg A., Ophelders D.R., De Munter S., Vanderlocht J., Germeraad W.T., Kuypers E., Collins J.J., Cleutjens J.P., Jennekens W., Gavilanes A.W., Seehase M., Vles H.J., Steinbusch H., Andriessen P., Wolfs T.G., Kramer B.W. Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep. J. Neuroinflammation. 2013; 10: 13.42. Winerdal M., Winerdal M.E., Kinn J., Urmaliya V., Winqvist O., Adén U. Long lasting local and systemic inflammation after cerebral hypoxic ischemia in newborn mice. PLoS One. 2012; 7 (5): 36422.43. Wanqiu Chen, Robert P. Ostrowski, Andre Obenaus, and John H. Zhang Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury. Exp Neurol. 2009; 216 (1): 7-15.44. Salmina A.B., Okuneva O.S., Malinovskaya N.A., Taranushenko T.E., Morgun A.V., Mantorova N.S., Mikhutkina S.V. Neirokhimiya = Neurochemistry. 2008; 25(3): 247–254.45. Salmina A.B., Okuneva O.S., Malinovskaya N.A., Zykova L.D., Fursov A.A., Morgun A.V., Mikhutkina S.V., Taranushenko T.E. Neirokhimiya = Neurochemistry. 2009; 26(3): 237–244.46. Golosnaya G.S., Petrukhin A.S., Krasil'shchikova T.M. Pediatriya = Pediatrics. 2010; 89(1): 20–25.47. Shruster A., Ben-Zur T., Melamed E., Offen D. Wnt signaling enhances neurogenesis and improves neurological function after focal ischemic injury. PLoS One. 2012; 7 (7): e40843.48. Al Haj Zen A, Madeddu P. Notch signalling in ischaemia-induced angiogenesis. Biochem. Soc. Trans. 2009; 37 (Pt 6): 1221-1227.49. Shimada I.S., Borders A., Aronshtam A., Spees J.L. Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke. Stroke. 2011; 42 (11): 3231-3237.50. del Zoppo G.J. Relationship of neurovascular elements to neuron injury during ischemia. Cerebrovasc. Dis. 2009; 27 (Suppl 1): 65-76.51. Lakhan S.E., Kirchgessner A., Tepper D., Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front. Neurol. 2013; 4: 32.52. Scholler K., Trinkl A., Klopotowski M., Thal S. C., Plesnila N., Trabold R., Hamann G.F., Schmid-Elsaesser R., Zausinger S. Characterization of microvascular basal lamina damage and blood-brain barrier dysfunction following subarachnoid hemorrhage in rats. Brain Res. 2007; 1142: 237-246.53. Sen E., Basu A., Willing L.B., Uliasz T.F., Myrkalo J.L., Vannucci S.J., Hewett S.J., Levison S.W. Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties. ASN Neuro. 2011; 3 (3): 62.54. Morgun A.V., Malinovskaya N.A., Okuneva O.S., Ustinova S.I., Karpova L.N., Salmina A.B., Pozhilenkova E.A., Laletin D.I., Frolova O.V., Kutishcheva I.A. Ekspressiya P-glikoproteina v kletkakh neirovaskulyarnoi edinitsy pri perinatal'noi gipoksii-ishemii mozga v ostrom periode. Sbornik tezisov dokladov X Vserossiiskoi nauchno-tekhnicheskoi konferentsii «Prioritetnye napravleniya razvitiya nauki i tekhnologii» [Expression of P-glycoprotein in Cells of Neurovascular Unit in Perinatal Cerebral Hypoxia-ischemia in Acute Period. Collection of Abstracts of X Russian Scientific-Technical Conference “Priority Directions of Science and Technology Development”]. Tula, "Innovatsionnye tekhnologii', 2011. pp. 115–116.55. Sizonenko S.V., Camm E.J., Dayer A., Kiss J.Z. Glial responses to neonatal hypoxic-ischemic injury in the rate cerebral cortex. Int. J. Dec. Neurosci. 2008; 26: 37-45.56. Salmina A.B., Malinovskaya N.A., Okuneva O.S., Taranushenko T.E., Fursov A.A., Mikhutkina S.V., Morgun A.V., Prokopenko S.V., Zykova L.D. Byulleten' eksperimental'noi biologii i meditsiny = Bulletin of experimental biology and medicine. 2008; 146(12): 641–645.57. Wang N., De Vuyst E., Ponsaerts R., Boengler K., Palacios-Prado N., Wauman J., Lai C.P., De Bock M., Decrock E., Bol M., Vinken M., Rogiers V., Tavernier J., Evans W.H., Naus C.C., Bukauskas F.F., Sipido K.R., Heusch G., Schulz R., Bultynck G., Leybaert L. Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res. Cardiol. 2013; 108 (1): 309.58. Cowan D.B., Jones M., Garcia L.M., Noria S., del Nido P.J., McGowan F.X. Jr. Arterioscler. Thromb. Vasc. Biol. 2003; 23 (10): 1754-1760.59. Kondo R.P., Wang S.Y., John S.A., Weiss J.N., Goldhaber J.I. J. Mol. Cell Cardiol. 2000; 32 (10): 1859-1872.60. Davidson J.O., Green C.R., Nicholson L.F., Bennet L., Gunn A.J. Int. J. Mol. Sci. 2012; 13 (5): 6303-6319.61. Zehendner C.M., Librizzi L., de Curtis M., Kuhlmann C.R., Luhmann H.J. Caspase-3 contributes to ZO-1 and Cl-5 tight-junction disruption in rapid anoxic neurovascular unit damage. PLoS One. 2011; 6 (2): e16760.62. Chen F., Ohashi N., Li W., Eckman C., Nguyen J.H. Disruption of occludin and claudin-2 in brain endothelial cells in vitro and in brains of mice with acute liver failure. Hepatology. 2009; 50: 1914-1923.63. Won S.M., Lee J.H., Park U.J., Gwag J., Gwag B.J., Lee Y.B. Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats. Exp. Mol. Med. 2011; 43 (2): 121-128.64. Orellana J.A., von Bernhardi R., Giaume C., Sáez J.C. Glial hemichannels and their involvement in aging and neurodegenerative diseases. Rev. Neurosci. 2012; 23 (2): 163-177.65. Sawada N., Kim H.H., Moskowitz M.A., Liao J.K. Rac1 is a critical mediator of endothelium-derived neurotrophic activity. Sci. Signal. 2009 Mar 10; 2 (61): doi: 10.1126/scisignal.2000162.66. Raz L., Zhang Q.G., Zhou C.F., Han D., Gulati P., Yang L.C., Yang F., Wang R.M., Brann D.W. Role of Rac1 GTPase in NADPH oxidase activation and cognitive impairment following cerebral ischemia in the rat. PLoS One. 2010 Sep 7; 5 (9): e12606.67. Aslam M., Schluter K.D., Rohrbach S., Rafiq A., Nazli S., Piper H.M., Noll T., Schulz R., Gündüz D. Hypoxia-reoxygenation-induced endothelial barrier failure: role of RhoA, Rac1 and myosin light chain kinase. J Physiol. 2013; 591 (Pt 2): 461-73.68. Liu S., Agalliu D., Yu C., Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr. Pharm. Des. 2012; 18 (25): 3653-3662.69. Al Ahmad A., Gassmann M., Ogunshola O.O. Involvement of oxidative stress in hypoxia-induced blood-brain barrier breakdown. Microvasc. Res. 2012; 84 (2): 222-225.70. Zozulya A., Weidenfeller C., Galla H.J. Pericyte-endothelial cell interaction increases MMP-9 secretion at the blood-brain barrier in vitro. Brain Res. 2008; 1189: 1-11.71. Ishitsuka K., Ago T., Arimura K., Nakamura K., Tokami H., Makihara N., Kuroda J., Kamouchi M., Kitazono T. Neurotrophin production in brain pericytes during hypoxia: a role of pericytes for neuroprotection. Microvasc. Res. 2012; 83 (3): 352-359.