Протективные эффекты препарата нуклеотидной природы “Деринат” на течение и клеточные механизмы черепно-мозговой травмы в эксперименте

Черепно-мозговая травма является наиболее частой причиной смерти и инвалидности среди молодых людей, включая спортсменов и солдат, людей в возрасте до 45 лет в промышленно развитых странах, и представляет растущую проблему со здоровьем как в развивающихся странах, так и среди стареющих людей, лечение которых является серьезной проблемой современной медицины. Этот вид травм приводит ко многим видам расстройств и очень часто к инвалидности, что обуславливает необходимость разработки новых методов лечения травм головного мозга. В экспериментах на мышах изучали новый метод лечения травм головного мозга, в частности использовали натриевую соль дезоксирибонуклеиновой кислоты. Этот препарат известен как смесь пептидов с иммуномодулирующим действием, который широко используется для лечения воспалительных, аллергических и аутоаллергических процессов. Натриевая соль дезоксирибонуклеиновой кислоты (DNA) (Деринат), выделенная из икры русского осетра, является препаратом, эффективность применения которого  показана при лечении различных заболеваний. В настоящей работе показаны нейропротекторные, антиоксидантные и противовоспалительные эффекты «Дерината» на модели черепно-мозговой травмы (ЧМТ) у крыс. Внутрибрюшинная инъекция «Дерината» в течение 3 дней после ЧМТ снижает объем повреждения ткани мозга. Иммуногистохимический анализ позволил констатировать морфологические изменения клеток микроглии в коре головного мозга и гиппокампе через 7 дней после ЧМТ, которые значительно снижались при введении препарата, как и индуцированное ЧМТ накопление 8-оксогуанина (8-oxoG) – маркера окислительного повреждения. Для изучения клеточного механизма противовоспалительных эффектов использовали первичную культивированную мышиную микроглию с АТФ (50 мкм и 1 мм) в качестве вещества, высвобождающегося в месте повреждения, для имитации воспалительной реакции in vitro. Введение «Дерината» обуславливало повышение количества мРНК нейротрофического фактора глиальных клеток (GDNF) и фактора роста нервов (NGF) в присутствии АТФ, а уровень мРНК активатора тканевого плазминогена (tPA) снижался при действии АТФ в сочетании с «Деринатом» или без него. Хотя экспрессия мРНК интерлейкина-6 (IL6) не изменялась при действии АТФ, она возрастала при аппликации «Дерината». Те же показатели фактора-α некроза опухоли (TNFα) были значительно ингибированы. Комплекс полученных данных раскрывает механизмы иммуномодулирующего действия дезоксирибонуклеиновых кислот при ЧМТ.

1. Aisiku I.P., Yamal J.M., Doshi P., Benoit J.S., Gopinath S., Goodman J.C., Robertson C.S. Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit. Care., 2016, Vol. 20, 288. https://doi.org/10.1186/s13054-016-1470-7.

2. Armstead W.M., Bohman L.E., Riley J., Yarovoi S., Higazi A.A., Cines D.B. tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1. J. Neurotrauma, 2013, Vol. 30, no. 22, pp. 1898-1907.

3. Armstead W.M., Kiessling J.W., Riley J., Cines D.B., Higazi A.A. tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK. Neurol. Res., 2011, Vol. 33, no. 7, pp. 726-733.

4. Armstead W.M., Riley J., Yarovoi S., Cines D.B., Smith D.H., Higazi A.A. tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury. J. Neurotrauma, 2012, Vol. 29, no. 9, 1794-1802.

5. Başkaya M.K., Doğan A., Temiz C., Dempsey R.J. Application of 2,3,5-triphenyltetrazolium chloride staining to evaluate injury volume after controlled cortical impact brain injury: role of brain edema in evolution of injury volume. J. Neurotrauma, 2000, Vol. 17, no. 1, pp. 93-99.

6. Benedek A., Móricz K., Jurányi Z., Gigler G., Lévay G., Hársing L.G. Jr., Mátyus P., Szénási G., Albert M. Use of TTC staining for the evaluation of tissue injury in the early phases of reperfusion after focal cerebral ischemia in rats. Brain Res., 2006, Vol. 1116, no. 1, pp. 159-165.

7. Beppu K., Kosai Y., Kido M.A., Akimoto N., Mori Y., Kojima Y., Fujita K., Okuno Y., Yamakawa Y., Ifuku M., Shinagawa R., Nabekura J., Sprengel R., Noda M. Expression, subunit composition, and function of AMPA-type glutamate receptors are changed in activated microglia; possible contribution of GluA2 (GluR-B)-deficiency under pathological conditions. Glia, 2013, Vol. 61, no. 6, pp. 881-891.

8. Blennow K., Brody D.L., Kochanek P.M., Levin H., McKee A., Ribbers G.M., Yaffe K., Zetterberg H. Traumatic brain injuries. Nat. Rev. Dis. Primers, 2016, Vol. 2, 16084. https://doi.org/10.1038/nrdp.2016.84.

9. Cantu D., Walker K., Andresen L., Taylor-Weiner A., Hampton D., Tesco G., Dulla C.G. Traumatic brain injury increases cortical glutamate network activity by compromising GABAergic control. Cereb. Cortex, 2015, Vol. 25, no. 8, pp. 2306-2320.

10. Chen X., Chen C., Fan S., Wu S., Yang F., Fang Z., Fu H., Li Y. Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury. J. Neuroinflammation, 2018, Vol. 15, no. 1, 116. https://doi.org/10.1186/s12974-018-1151-3.

11. Cheong C.U., Chang C.P., Chao C.M., Cheng B.C., Yang C.Z., Chio C.C. Etanercept attenuates traumatic brain injury in rats by reducing brain TNF-α contents and by stimulating newly formed neurogenesis. Mediators Inflamm., 2013, Vol. 2013, 620837. https://doi.org/10.1155/2013/620837.

12. Chio C.C., Lin M.T., Chang C.P. Microglial activation as a compelling target for treating acute traumatic brain injury. Curr. Med. Chem., 2015, Vol. 22, no. 6, pp. 759-770.

13. Chiu C.C., Liao Y.E., Yang L.Y., Wang J.Y., Tweedie D., Karnati H.K., Greig N.H., Wang J.Y. Neuroinflammation in animal models of traumatic brain injury. J. Neurosci. Methods, 2016, Vol. 272, pp. 38-49.

14. Clark D.P.Q., Perreau V.M., Shultz S.R., Brady R.D., Lei E., Dixit S., Taylor J.M., Beart P.M., Boon W.C. Inflammation in Traumatic Brain Injury: Roles for toxic A1 astrocytes and microglial-astrocytic crosstalk. Neurochem. Res., 2019, Vol. 44, no. 6, pp. 1410-1424.

15. Corrigan F., Mander K.A., Leonard A.V., Vink R. Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation. J. Neuroinflammation, 2016, Vol. 13, no. 1, 264. https://doi.org/10.1186/s12974-016-0738-9.

16. Cotrina M.L., Chen M., Han X., Iliff J., Ren Z., Sun W., Hagemann T., Goldman J., Messing A., Nedergaard M. Effects of traumatic brain injury on reactive astrogliosis and seizures in mouse models of Alexander disease. Brain Res., 2014, Vol. 1582, pp. 211-219.

17. Dalla Libera A.L., Regner A., de Paoli J., Centenaro L., Martins T.T., Simon D. IL-6 polymorphism associated with fatal outcome in patients with severe traumatic brain injury. Brain Inj., 2011, Vol. 25, no. 4, pp. 365-936.

18. Daoud H., Alharfi I., Alhelali I., Charyk Stewart T., Qasem H., Fraser D.D. Brain injury biomarkers as outcome predictors in pediatric severe traumatic brain injury. Neurocrit. Care, 2014, Vol. 20, no. 3, pp. 427-435.

19. Davalos D., Grutzendler J., Yang G., Kim J.V., Zuo Y., Jung S., Littman D.R., Dustin M.L., Gan W.B. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci., 2005, Vol. 8, no. 6, pp. 752-758.

20. Dmitrienko E.V., Filatenkova T.A., Rybakina E.G., Korneva E.A. Behavioral reactions of animals after experimental traumatic brain injury: Effects of the nucleotide drug nature. Bulletin of St. Petersburg University, 2014, Vol. 11, no. 3, pp. 180-191.

21. Du G., Zhao Z., Chen Y., Li Z., Tian Y., Liu Z., Liu B., Song J. Quercetin protects rat cortical neurons against traumatic brain injury. Mol. Med. Rep., 2018, Vol. 17, no. 6, pp. 7859-7865.

22. Finan J.D. Biomechanical simulation of traumatic brain injury in the rat. Clin. Biomech., 2019, Vol. 64, pp. 114-121.

23. Fomicheva E.E., Filatenkova T.A., Shanin S.N., Rybakina E.G. Stress-induced changes in the functional activity of the neuroendocrine system: the modulatory activity of derinat. Neurosci. Behav. Physiol., 2010, Vol. 40, no. 4, pp. 397-401.

24. Fujita K., Seike T., Yutsudo N., Ohno M., Yamada H., Yamaguchi H., Sakumi K., Yamakawa Y., Kido M.A., Takaki A., Katafuchi T., Tanaka Y., Nakabeppu Y., Noda M. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One, 2009, Vol. 4, no. 9, e7247. https://doi.org/10.1371/journal.pone.0007247.

25. Gatson J.W., Liu M.M., Abdelfattah K., Wigginton J.G., Smith S., Wolf S., Minei J.P. Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury. J. Trauma Acute Care Surg., 2013, Vol. 74, no. 2, pp. 470-475.

26. Ghajar J. Traumatic brain injury. Lancet, 2000, Vol. 356, no. 9233, pp. 923-929.

27. Grummisch J.A., Jadavji N.M., Smith P.D. tPA promotes cortical neuron survival via mTOR-dependent mechanisms. Mol. Cell. Neurosci., 2016, Vol. 74, pp. 25-33.

28. Hagino Y., Kariura Y., Manago Y., Amano T., Wang B., Sekiguchi M., Nishikawa K., Aoki S., Wada K., Noda M. Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia. Glia, 2004, Vol. 47, no. 1, pp. 68-77.

29. Hanlon L.A., Raghupathi R., Huh J.W. Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology. Exp. Neurol., 2019, Vol. 316, pp. 39-51.

30. Harvey L.D., Yin Y., Attarwala I.Y., Begum G., Deng J., Yan H.Q., Dixon C.E., Sun D. Administration of DHA reduces endoplasmic reticulum stress-associated inflammation and alters microglial or macrophage activation in traumatic brain injury. ASN Neuro, 2015, Vol. 7, no. 6, 1759091415618969. https://doi.org/10.1177/1759091415618969.

31. Henry R.J., Ritzel R.M., Barrett J.P., Doran S.J., Jiao Y., Leach J.B., Szeto G.L., Wu J., Stoica B.A., Faden A.I., Loane D.J. Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. J. Neurosci., 2020, Vol. 40, no. 14, pp. 2960-2974.

32. Hide I., Tanaka M., Inoue A., Nakajima K., Kohsaka S., Inoue K., Nakata Y. Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J. Neurochem., 2000, Vol. 75, no. 3, pp. 965-972.

33. Hijazi N., Abu Fanne R., Abramovitch R., Yarovoi S., Higazi M., Abdeen S., Basheer M., Maraga E., Cines D.B., Higazi A.A. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood, 2015, Vol. 125, no. 16, pp. 2558-2567.

34. Hsu W.L., Lu J.H., Noda M., Wu C.Y., Liu J.D., Sakakibara M., Tsai M.H., Yu H.S., Lin M.W., Huang Y.B., Yan S.J., Yoshioka T. Derinat protects skin against utraviolet-B (UVB)-induced cellular damage. Molecules, 2015, Vol. 20, no. 11, pp. 20297-20311.

35. Hu B.Y., Liu X.J., Qiang R., Jiang Z.L., Xu L.H., Wang G.H., Li X., Peng B. Treatment with ginseng total saponins improves the neurorestoration of rat after traumatic brain injury. J. Ethnopharmacol., 2014, Vol. 155, no. 2, pp. 1243-1255.

36. Imai Y., Ibata I., Ito D., Ohsawa K., Kohsaka S. A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem. Biophys. Res. Commun., 1996, Vol. 224, no. 3, pp. 855-862.

37. Jassam Y.N., Izzy S., Whalen M., McGavern D.B., El Khoury J. Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron, 2017, Vol. 95, no. 6, pp. 1246-1265.

38. Jayakumar A.R., Tong X.Y., Ruiz-Cordero R., Bregy A., Bethea J.R., Bramlett H.M., Norenberg M.D. Activation of NF-κB mediates astrocyte swelling and brain edema in traumatic brain injury. J. Neurotrauma, 2014, Vol. 31, no. 14, pp. 1249-1257.

39. Joy M.T., Ben Assayag E., Shabashov-Stone D., Liraz-Zaltsman S., Mazzitelli J., Arenas M., Abduljawad N., Kliper E., Korczyn A.D., Thareja N.S., Kesner E.L., Zhou M., Huang S., Silva T.K., Katz N., Bornstein N.M., Silva A.J., Shohami E., Carmichael S.T. CCR5 Is a therapeutic target for recovery after stroke and traumatic brain injury. Cell, 2019, Vol. 176, no. 5, pp. 1143-1157.e13.

40. Karve I.P., Taylor J.M., Crack P.J. The contribution of astrocytes and microglia to traumatic brain injury. Br. J. Pharmacol., 2016, Vol. 173, no. 4, pp. 692-702.

41. Kettenmann H., Hanisch U.K., Noda M., Verkhratsky A. Physiology of microglia. Physiol. Rev., 2011, Vol. 91, no. 2, pp. 461-553.

42. Kim E.J., Kim S.Y., Lee J.H., Kim J.M., Kim J.S., Byun J.I., Koo B.N. Effect of isoflurane post-treatment on tPA-exaggerated brain injury in a rat ischemic stroke model. Korean J. Anesthesiol., 2015, Vol. 68, no. 3, pp. 281-286.

43. Krukowski K., Chou A., Feng X., Tiret B., Paladini M.S., Riparip L.K., Chaumeil M.M., Lemere C., Rosi S. Traumatic brain injury in aged mice induces chronic microglia activation, synapse loss, and complement-dependent memory deficits. Int. J. Mol. Sci., 2018, Vol. 19, no. 12, 3753. https://doi.org/10.3390/ijms19123753.

44. Kumar A., Henry R.J., Stoica B.A., Loane D.J., Abulwerdi G., Bhat S.A., Faden A.I. Neutral sphingomyelinase inhibition alleviates lps-induced microglia activation and neuroinflammation after experimental traumatic brain injury. J. Pharmacol. Exp. Ther., 2019, Vol. 368, no. 3, pp. 338-352.

45. Kumar A., Stoica B.A., Loane D.J., Yang M., Abulwerdi G., Khan N., Kumar A., Thom S.R., Faden A.I. Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury. J. Neuroinflammation, 2017, Vol. 14, 47. https://doi.org/10.1186/s12974-017-0819-4.

46. Kumar R.G., Diamond M.L., Boles J.A., Berger R.P., Tisherman S.A., Kochanek P.M., Wagner A.K. Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome. Brain Behav. Immun., 2015, Vol. 45, pp. 253-262.

47. Lee S.H., Ko H.M., Kwon K.J., Lee J., Han S.H., Han D.W., Cheong J.H., Ryu J.H., Shin C.Y. tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells. Mol. Neurobiol., 2014, Vol. 49, no. 1, pp. 199-215.

48. Lewén A., Sugawara T., Gasche Y., Fujimura M., Chan P.H. Oxidative cellular damage and the reduction of APE/Ref-1 expression after experimental traumatic brain injury. Neurobiol. Dis., 2001, Vol. 8, no. 3, pp. 380-390.

49. Lin B.S., Wang C.C., Chang M.H., Chio C.C. Evaluation of traumatic brain injury by optical technique. BMC Neurol., 2015, Vol. 15, 202. https://doi.org/10.1186/s12883-015-0465-3.

50. Lindh C., Wennersten A., Arnberg F., Holmin S., Mathiesen T. Differences in cell death between high and low energy brain injury in adult rats. Acta Neurochir., 2008, Vol. 150, no. 12, pp. 1269-1275.

51. Liu J., Rybakina E.G., Korneva E.A., Noda M. Effects of Derinat on ischemia-reperfusion-induced pressure ulcer mouse model. J. Pharmacol. Sci., 2018, Vol. 138, no. 2, pp. 123-130.

52. Loane D.J., Kumar A. Microglia in the TBI brain: The good, the bad, and the dysregulated. Exp. Neurol., 2016, Vol. 275, no. 3, pp. 316-327.

53. Long X., Yao X., Jiang Q., Yang Y., He X., Tian W., Zhao K., Zhang H. Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury. J. Neuroinflammation, 2020, Vol. 17, no. 1, 89. https://doi.org/10.1186/s12974-020-01761-0.

54. Lorente L., Martín M.M., González-Rivero A.F., Pérez-Cejas A., Abreu-González P., Ramos L., Argueso M., Cáceres J.J., Solé-Violán J., Alvarez-Castillo A., Jiménez A., García-Marín V. Association between DNA and RNA oxidative damage and mortality of patients with traumatic brain injury. Neurocrit. Care, 2020, Vol. 32, no. 3, pp. 790-795.

55. Lu J., Frerich J.M., Turtzo L.C., Li S., Chiang J., Yang C., Wang X., Zhang C., Wu C., Sun Z., Niu G., Zhuang Z., Brady R.O., Chen X. Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury. Proc. Natl. Acad. Sci. USA, 2013, Vol. 110, no. 26, pp. 10747-10752.

56. Lv Q., Lan W., Sun W., Ye R., Fan X., Ma M., Yin Q., Jiang Y., Xu G., Dai J., Guo R., Liu X. Intranasal nerve growth factor attenuates tau phosphorylation in brain after traumatic brain injury in rats. J. Neurol. Sci., 2014, Vol. 345, no. 1-2, pp. 48-55.

57. Ma J., Ni H., Rui Q., Liu H., Jiang F., Gao R., Gao Y., Li D., Chen G. Potential roles of NIX/BNIP3L pathway in rat traumatic brain injury. Cell Transplant., 2019, Vol. 28, no. 5, pp. 585-595.

58. Madathil S.K., Carlson S.W., Brelsfoard J.M., Ye P., D’Ercole A.J., Saatman K.E. Astrocyte-specific overexpression of insulin-like growth factor-1 protects hippocampal neurons and reduces behavioral deficits following traumatic brain injury in mice. PLoS One, 2013, Vol. 8, no. 6, e67204. https://doi.org/10.1371/journal.pone.0067204.

59. Makinde H.M., Just T.B., Gadhvi G.T., Winter D.R., Schwulst S.J. Microglia adopt longitudinal transcriptional changes after traumatic brain injury. J. Surg. Res., 2020, Vol. 246, pp. 113-122.

60. Markkanen E. Not breathing is not an option: How to deal with oxidative DNA damage. DNA Repair, 2017, Vol. 59, pp. 82-105.

61. Marklund N. Rodent models of traumatic brain injury: methods and challenges. Methods Mol. Biol., 2016, Vol. 1462, pp. 29-46.

62. Marmarou C.R., Liang X., Abidi N.H., Parveen S., Taya K., Henderson S.C., Young H.F., Filippidis A.S., Baumgarten C.M. Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury. Brain Res., 2014, Vol. 1581, pp. 89-102.

63. McKee A.C., Robinson M.E. Military-related traumatic brain injury and neurodegeneration. Alzheimers Dementia, 2014, Vol. 10, no. 3, pp. S242-S253.

64. McMahon P.J., Panczykowski D.M., Yue J.K., Puccio A.M., Inoue T., Sorani M.D., Lingsma H.F., Maas A.I., Valadka A.B., Yuh E.L., Mukherjee P., Manley G.T., Okonkwo D.O. TRACK-TBI Investigators. Measurement of the glial fibrillary acidic protein and its breakdown products GFAP-BDP biomarker for the detection of traumatic brain injury compared to computed tomography and magnetic resonance imaging. J. Neurotrauma, 2015, Vol. 32, no. 8, pp. 527-33.

65. Medcalf R.L. The traumatic side of fibrinolysis. Blood, 2015, Vol. 125, no. 16, pp. 2457-2458.

66. Meng Y., Chopp M., Zhang Y., Liu Z., An A., Mahmood A., Xiong Y. Subacute intranasal administration of tissue plasminogen activator promotes neuroplasticity and improves functional recovery following traumatic brain injury in rats. PLoS One, 2014, Vol. 9, no. 9, e106238. https://doi.org/10.1371/journal.pone.0106238.

67. Mori Y., Tomonaga D., Kalashnikova A., Furuya F., Akimoto N., Ifuku M., Okuno Y., Beppu K., Fujita K., Katafuchi T., Shimura H., Churilov L.P., Noda M. Effects of 3,3’,5-triiodothyronine on microglial functions. Glia, 2015, Vol. 63, no. 5, pp. 906-920.

68. Needham E.J., Helmy A., Zanier E.R., Jones J.L., Coles A.J., Menon D.K. The immunological response to traumatic brain injury. J. Neuroimmunol., 2019, Vol. 332, pp. 112-125.

69. Nimmerjahn A., Kirchhoff F., Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 2005, Vol. 308, no. 5726, pp. 1314-1318.

70. Ohno M., Oka S., Nakabeppu Y. Quantitative analysis of oxidized guanine, 8-oxoguanine, in mitochondrial DNA by immunofluorescence method. Methods Mol. Biol., 2009, Vol. 554, pp. 199-212.

71. Ohsawa K., Kohsaka S. Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia, 2011, Vol. 59, no. 12, pp. 1793-1799.

72. Oka S., Ohno M., Tsuchimoto D., Sakumi K., Furuichi M., Nakabeppu Y. Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. EMBO J., 2008, Vol. 27, no. 2, pp. 421-432.

73. Papa L., Silvestri S., Brophy G.M., Giordano P., Falk J.L., Braga C.F., Tan C.N., Ameli N.J., Demery J.A., Dixit N.K., Mendes M.E., Hayes R.L., Wang K.K., Robertson C.S. GFAP out-performs S100β in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. J. Neurotrauma, 2014, Vol. 31, no. 22, pp. 1815-1822.

74. Perri B.R., Smith D.H., Murai H., Sinson G., Saatman K.E., Raghupathi R., Bartus R.T., McIntosh T.K. Metabolic quantification of lesion volume following experimental traumatic brain injury in the rat. J. Neurotrauma, 1997, Vol. 14, no. 1, pp. 15-22.

75. Rowe R.K., Striz M., Bachstetter A.D., Van Eldik L.J., Donohue K.D., O’Hara B.F., Lifshitz J. Diffuse brain injury induces acute post-traumatic sleep. PLoS One, 2014, Vol. 9, no. 1, e82507. https://doi.org/10.1371/journal.pone.0082507.

76. Schober M.E., Requena D.F., Rodesch C.K. EPO improved neurologic outcome in rat pups late after traumatic brain injury. Brain Dev., 2018, Vol. 40, no. 5, pp. 367-375.

77. Scrimgeour A.G., Condlin M.L. Nutritional treatment for traumatic brain injury. J. Neurotrauma, 2014, Vol. 31, no. 11, pp. 989-999.

78. Shen Q., Yin Y., Xia Q.J., Lin N., Wang Y.C., Liu J., Wang H.P., Lim A., Wang T.H. Bone Marrow Stromal Cells Promote Neuronal Restoration in Rats with Traumatic Brain Injury: Involvement of GDNF Regulating BAD and BAX Signaling. Cell. Physiol. Biochem., 2016, Vol. 38, no. 2, pp. 748-762.

79. Song S., Kong X., Acosta S., Sava V., Borlongan C., Sanchez-Ramos J. Granulocyte colony-stimulating factor promotes behavioral recovery in a mouse model of traumatic brain injury. J. Neurosci. Res., 2016, Vol. 94, no. 5, pp. 409-423.

80. Thal S.C., Wyschkon S., Pieter D., Engelhard K., Werner C. Selection of endogenous control genes for normalization of gene expression analysis after experimental brain trauma in mice. J. Neurotrauma, 2008, Vol. 25, no. 7, pp. 785-794.

81. Timmerman K.L., Amonette W.E., Markofski M.M., Ansinelli H.A., Gleason E.A., Rasmussen B.B., Mossberg K.A. Blunted IL-6 and IL-10 response to maximal aerobic exercise in patients with traumatic brain injury. Eur. J. Appl. Physiol., 2015, Vol. 115, no. 1, pp. 111-118.

82. Tobinick E., Kim N.M., Reyzin G., Rodriguez-Romanacce H., DePuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs, 2012, Vol. 26, no. 12, pp. 1051-1070.

83. Tuttolomondo A., Pecoraro R., Pinto A. Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date. Drug Des. Devel. Ther., 2014, Vol. 8, pp. 2221-2238.

84. Wang Y., Chen D., Chen G. Hyperbaric oxygen therapy applied research in traumatic brain injury: from mechanisms to clinical investigation. Med. Gas. Res., 2014, Vol. 4, 18. https://doi.org/10.1186/2045-9912-4-18.

85. Wang Y., Yue X., Kiesewetter D.O., Niu G., Teng G., Chen X. PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714. Eur. J. Nucl. Med. Mol. Imaging, 2014, Vol. 41, no. 7, pp. 1440-1449.

86. Willis E.F., MacDonald K.P.A., Nguyen Q.H., Garrido A.L., Gillespie E.R., Harley S.B.R., Bartlett P.F., Schroder W.A., Yates A.G., Anthony D.C., Rose-John S., Ruitenberg M.J., Vukovic J. Repopulating microglia promote brain repair in an IL-6-dependent manner. Cell, 2020, Vol.180, no. 5, pp. 833-846.e16.

87. Witcher K.G., Bray C.E., Dziabis J.E., McKim D.B., Benner B.N., Rowe R.K., Kokiko-Cochran O.N., Popovich P.G., Lifshitz J., Eiferman D.S., Godbout J.P. Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation. Glia, 2018, Vol. 66, no. 12, pp. 2719-2736.

88. Xing P., Ma K., Li L., Wang D., Hu G., Long W. The protection effect and mechanism of hyperbaric oxygen therapy in rat brain with traumatic injury. Acta Cir. Bras., 2018, Vol. 33, no. 4, pp. 341-353.

89. Xu B., Yu D.M., Liu F.S. Effect of siRNA-induced inhibition of IL-6 expression in rat cerebral gliocytes on cerebral edema following traumatic brain injury. Mol. Med. Rep., 2014, Vol. 10, no. 4, pp. 1863-1868.

90. Yamaguchi H., Kajitani K., Dan Y., Furuichi M., Ohno M., Sakumi K., Kang D., Nakabeppu Y. MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Cell Death Differ., 2006, Vol. 13, no. 4, pp. 551-563.

91. Yang Y., Ye Y., Kong C., Su X., Zhang X., Bai W., He X. MiR-124 enriched exosomes promoted the M2 polarization of microglia and enhanced hippocampus neurogenesis after traumatic brain injury by inhibiting TLR4 pathway. Neurochem. Res., 2019, Vol. 44, no. 4, pp. 811-828.

92. Younger D., Murugan M., Rama Rao K.V., Wu L.J., Chandra N. Microglia receptors in animal models of traumatic brain injury. Mol. Neurobiol., 2019, Vol. 56, no. 7, pp. 5202-5228.

93. Zhao J., Wang B., Huang T., Guo X., Yang Z., Song J., Zhang M. Glial response in early stages of traumatic brain injury. Neurosci. Lett., 2019, Vol. 708, 134335. https://doi.org/10.1016/j.neulet.2019.134335.

94. Zhuang Y.F., Li J. Serum EGF and NGF levels of patients with brain injury and limb fracture. Asian Pac. J. Trop. Med., 2013, Vol. 6, no. 5, pp. 383-386.