Postresuscitative Changes of Brain-Derived Neurotrophic Factor (BDNF) Protein Expression: Association With Neuronal Death

Aim of the study: to evaluate expression level of BDNF and its association with the postresuscitative neuronal death in highly hypoxia-sensitive brain regions.

Materials and methods. Cardiac arrest in adult albino male rats was evoked by intrathoracic clamping of supracardiac bundle of vessels for 10 min. Pyramidal neurons of the hippocampus and Purkinje cells of the cerebellum were analyzed at various time points after resuscitation (days 1, 4, 7, 14). Shame-operated rats served as controls. The expression of BDNF protein was immunohistochemically determined. The BDNF expression level was determined by evalution on the base of the average optical density. The number of neurons with different BDNF expression levels and the total number of neurons per 1 mm of the layer length were computed. Image analysis systems (Intel personal computer, Olympus BX-41 microscope, ImageScopeM, ImageJ 1,48v and MS Excel 2007 software packages) were used in the study. Data statistical processing was performed with the aid of Statistica 7.0 program and Kolmogorov-Smirnov λ-test, Mann-Whitney U-test and Student's t-test.

Results. The dynamics of postresuscitative shifts of BDNF immunoreactivity in neuronal populations of hippocampal pyramidal cells and cerebellar Purkinje cells was established. It was shown that the level of BDNF expression within the two neuronal populations decreased, that was accompanied by neuronal death. In the Purkinje cell population the neuronal death occurred by the 4th day after resuscitation, while in the hippocampus, it occurs only by the 7th day. Notably, only BDNF-negative neurons or neurons with low level of BDNF expression died in both neuronal populations.

Conclusion. The results of the study indicate the existence of an interrelation between the shifts in BDNF expression and the postresuscitative neuronal death. It was shown that only the cells with none or poor BDNF expression underwent death in highly hypoxia-sensitive neuronal populations. The results suggest that the level of BDNF expression is one of factors that have a significant effect on neuronal resistance to ischemia-reperfusion. A possibility of induction of the endogenous BDNF expression in order to prevent neuronal death is discussed. 

1. Avrushchenko M.Sh., Moroz V.V., Ostrova I.V. Postresuscitation changes in the brain at the level of neuronal populations: patterns and mecha- nisms. Obshchaya Reanimatologiya = General Reanimatology. 2012; 8 (4): 69-78. DOI: 10.15360/1813-9779-2012-4-69. [In Russ., In Engl.]

2. Avrushchenko M.Sh., Ostrova I.V., Volkov A.V., Zarzhetsky Yu.V. Postresuscitative changes in the morphofunctional state of nerve cells: implication in the pathogenesis of encephalopathies. Obshchaya Reanimatologiya = General Reanimatology. 2006; 2 (5-6): 85-97. DOI: 10.15360/1813-9779-2006-6-85-96. [In Russ., In Engl.]

3. Ostrova I.V., Avrushchenko M.S. Expression of Brain-Derived Neurotrophic Factor (BDNF) increases the resistance of neurons to death in the postresuscitation period. Obshchaya Reanimatologiya = General Reanimatology. 2015; 11 (3): 45-53. DOI: 10.15360/1813- 9779-2015-3-45-53. [In Russ., In Engl.]

4. Ostrova I.V., Moroz V.V., Avrushchenko M.Sh. Significance of immuno- histochemical studies of heat shock proteins of the HSP70 family in the investigation of postresuscitative brain changes. Obshchaya Reanimatologiya = General Reanimatology. 2007; 3 (5-6): 91-96. DOI: 10.15360/1813-9779-2007-6-91-96. [In Russ., In Engl.]

5. Ostrova I.V., Avrushchenko M.Sh., Volkov A.V. Association of GRP78 protein expression with the degree of postischemic hippocampal dam- age in rats of both sexes. Obshchaya Reanimatologiya = General Reanimatology. 2011; 7 (6): 28-33. DOI: 10.15360/1813-9779-2011-6- 28. [In Russ., In Engl.]

6. Avrushchenko M.Sh., Ostrova I.V., Volkov A.V. Postresuscitation changes in the expression of GlialDerived Neurotrophic Factor (GDNF): associ- ation with cerebellar Purkinje cell damage (an experimental study). Obshchaya Reanimatologiya = General Reanimatology. 2014; 10 (5): 59- 68. DOI: 10.15360/1813-9779-2014-5-59-68. [In Russ., In Engl.]

7. Avrushchenko M.Sh., Ostrova I.V. Significance of Basic Fibroblast Growth Factor (BFGF) in the development of postresuscitation changes in population of cerebellar Purkinje cells. Obshchaya Reanimatologiya = General Reanimatology. 2016; 12 (1): 8-15. DOI: 10.15360/1813-9779-2016-1-8-15. [In Russ., In Engl.]

8. Larpthaveesarp A., Ferriero D.M., Gonzalez F.F. Growth factors for the treatment of ischemic brain injury (growth factor treatment). Brain Sci. 2015; 5 (2): 165-177. DOI: 10.3390/brainsci5020165. PMID: 25942688

9. Kimura A., Namekata K., Guo X., Harada C., Harada T. Neuroprotection, growth factors and BDNF-TrkB signalling in retinal degeneration. Int. J. Mol. Sci. 2016; 17 (9): pii: E1584. DOI: 10.3390/ijms17091584. PMID: 27657046

10. Gray J.D., Milner T.A., McEwen B.S. Dynamic plasticity: the role of glu- cocorticoids, brain-derived neurotrophic factor and other trophic fac- tors. Neuroscience. 2013; 239: 214-227. DOI: 10.1016/j.neuro- science.2012.08.034. PMID: 22922121

11. Hempstead B.L. Brain-derived neurotrophic factor: three ligands, many actions. Trans. Am. Clin. Climatol. Assoc. 2015; 126: 9-19. PMID: 26330656

12. Bowling H., Bhattacharya A., Klann E., Chao M.V. Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. Neural. Regen. Res. 2016; 11 (3): 363–367. DOI: 10.4103/1673-5374.179031. PMID: 27127458

13. Garraway S.M., Huie J.R. Spinal plasticity and behavior: BDNF- induced neuromodulation in uninjured and injured spinal cord. Neural. Plast. 2016; 2016: 9857201. DOI: 10.1155/2016/9857201. PMID: 27721996

14. Berretta A., Tzeng Y.C., Clarkson A.N. Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor. Expert Rev. Neurother. 2014; 14 (11): 1335-1344. DOI: 10.1586/14737175.2014.969242. PMID: 25319267

15. Blondeau N., Lipsky R.H., Bourourou M., Duncan M.W., Gorelick P.B., Marini A.M. Alpha-linolenic acid: an omega-3 fatty acid with neuro- protective properties-ready for use in the stroke clinic? Biomed. Res. Int. 2015; 2015: 519830. DOI: 10.1155/2015/519830. PMID: 25789320

16. Budni J., BellettiniSantos T., Mina F., Garcez M.L., Zugno A.I. The involvement of BDNF, NGF and GDNF in aging and Alzheimer’s dis- ease. Aging Dis. 2015; 6 (5): 331-341. DOI: 10.14336/AD.2015.0825. PMID: 26425388

17. Khalin I., Alyautdin R., Kocherga G., Bakar M.A. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness. Int. J. Nanomedicine. 2015; 10: 3245-3267. DOI: 10.2147/IJN.S77480. PMID: 25995632

18. Dincheva I., Lynch N.B., Lee F.S. The role of BDNF in the development of fear learning. Depress. Anxiety. 2016; 33 (10): 907-916. DOI: 10.1002/da.22497. PMID: 27699937

19. Liu C., Chan C.B., Ye K. 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disor- ders. Transl. Neurodegener. 2016; 5: 2. DOI: 10.1186/s40035-015-0048- 7. PMID: 26740873

20. Blaha G.R., Raghupathi R., Saatman K.E., McIntosh T.K. Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits. Neuroscience. 2000; 99 (3): 483-493. DOI: 10.1016/S0306- 4522(00)00214-1. PMID: 11029540

21. Hoshaw B.A., Malberg J.E., Lucki I. Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res. 2005; 1037 (1-2): 204-208. DOI: 10.1016/j.brainres.2005.01.007. PMID: 15777771

22. Nagahara A.H., Merrill D.A., Coppola G., Tsukada S., Schroeder B.E., Shaked G.M., Wang L., Blesch A., Kim A., Conner J.M., Rockenstein E., Chao M.V., Koo E.H., Geschwind D., Masliah E., Chiba A.A., Tuszynski M.H. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat. Med. 2009; 15 (3): 331-337. DOI: 10.1038/nm.1912. PMID: 19198615

23. Makar T.K., Bever C.T., Singh I.S., Royal W., Sahu S.N., Sura T.P., Sultana S., Sura K.T., Patel N., DhibJalbut S., Trisler D. Brain-derived neu- rotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J. Neuroimmunol. 2009; 210 (1-2): 40-51. DOI: 10.1016/j.jneuroim.2009.02.017. PMID: 19361871

24. Yang J.L., Lin Y.T., Chuang P.C., Bohr V.A., Mattson M.P. BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease. Neuromolecular Med. 2014; 16 (1): 161-174. DOI: 10.1007/s12017-013-8270-x. PMID: 24114393

25. Otis J.M., Fitzgerald M.K., Mueller D. Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine- conditioned place preference. J. Neurosci. 2014; 34 (17): 6057-6064. DOI: 10.1523/JNEUROSCI.4980-13.2014. PMID: 24760865

26. Koeva Y.A., Sivkov S.T., Akabaliev V.H., Ivanova R.Y., Deneva T.I., Grozlekova L.S., Georgieva V. Brain-derived neurotrophic factor and its serum levels in schizophrenic patients. Folia. Med. (Plovdiv). 2014; 56 (1): 20-23. DOI: 10.2478/folmed-2014-0003. PMID: 24812918

27. Dong E., Dzitoyeva S.G., Matrisciano F., Tueting P., Grayson D.R., Guidotti A. Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice. Biol. Psychiatry. 2015; 77 (6): 589-596. DOI: 10.1016/j.biopsych.2014.08.012. PMID: 25444166

28. Deng P., Torrest A., Pollock K., Dahlenburg H., Annett G., Nolta J.A., Fink K.D. Clinical trial perspective for adult and juvenile Huntington’s disease using genetically-engineered mesenchymal stem cells. Neural. Regen. Res. 2016; 115): 702-705. DOI: 10.4103/1673-5374.182682. PMID: 27335539

29. Schäbitz W.R., Sommer C., Zoder W., Kiessling M., Schwaninger M., Schwab S. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulatesBax and Bcl-2 expression after tempo- rary focal cerebral ischemia. Stroke. 2000; 31 (9): 2212-2217. DOI: 10.1161/01.STR.31.9.2212. PMID: 10978054

30. Schäbitz W.R., Steigleder T., Cooper-Kuhn C.M., Schwab S., Sommer C., Schneider A., Kuhn H.G. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogene- sis. Stroke. 2007; 38 (7): 2165-2172. DOI: 10.1161/STROKEA- HA.106.477331. PMID: 17510456

31. Ferrer I., Krupinski J., Goutan E., Martí E., Ambrosio S., Arenas E. Brain- derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat. Acta Neuropathol. 2001; 101 (3): 229-238. PMID: 11307622

32. Kurozumi K., Nakamura K., Tamiya T., Kawano Y., Kobune M., Hirai S., Uchida H., Sasaki K., Ito Y., Kato K., Honmou O., Houkin K., Date I., Hamada H. BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol. Ther. 2004; 9 (2): 189-197. DOI: 10.1016/j.ymthe.2003.10.012. PMID: 14759803

33. Zhang Y., Qiu B., Wang J., Yao Y., Wang C., Liu J. Effects of BDNF-trans- fected BMSCs on neural functional recovery and synaptophysin expression in rats with cerebral infarction. Mol. Neurobiol. 2017; 54 (5): 3813-3824. DOI: 0.1007/s12035-016-9946-7. PMID: 27282770

34. MacLellan C.L., Keough M.B., GranterButton S., Chernenko G.A., Butt S., Corbett D. Acritical threshold of rehabilitation involving brain- derived neurotrophic factor is required for poststroke recovery. Neurorehabil. Neural. Repair. 2011; 25 (8): 740-748. DOI: 10.1177/1545968311407517. PMID: 21705652

35. Jiang Y., Wei N., Lu T., Zhu J., Xu G., Liu X. Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats. Neuroscience. 2011; 172: 398-405. DOI: 10.1016/j.neuroscience.2010.10.054. PMID: 21034794

36. van Velthoven C.T., Sheldon R.A., Kavelaars A., Derugin N., Vexler Z.S., Willemen H.L., Maas M., Heijnen C.J., Ferriero D.M. Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke. 2013; 44 (5): 1426-1432. DOI: 10.1161/STROKEA- HA.111.000326. PMID: 23539530

37. Miyake K., Yamamoto W., Tadokoro M., Takagi N., Sasakawa K., Nitta A., Furukawa S., Takeo S. Alterations in hippocampal GAP-43, BDNF, and L1 following sustained cerebral ischemia. Brain Res. 2002; 935 (1-2): 24-31. DOI: 10.1016/S0006-8993(02)02420-4. PMID: 12062469 3

38. chida H., Yokoyama H., Kimoto H., Kato H., Araki T. Long-term changes in the ipsilateral substantia nigra after transient focal cerebral ischaemia in rats. Int. J. Exp. Pathol. 2010; 91 (3): 256-266. DOI: 10.1111/j.1365-2613.2010.00712.x. PMID: 20353427

39. Stavchanski V.V., Tvorogova T.V., Botsina A.Iu., Skvortsova V.I., Limborskaia S.A., Miasoedov N.F., Dergunova L.V. The effect of semax and its C-end peptide PGP on expression of the neurotrophins and their receptors in the rat brain during incomplete global ischemia. Mol. Biol. (Mosk). 2011; 45 (6): 1026-1035. PMID: 22295573. [In Russ.]

40. Shu X., Zhang Y., Xu H., Kang K., Cai D. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia. Neural. Regen. Res. 2013; 8 (25): 2370-2378. DOI: 10.3969/j.issn.1673- 5374.2013.25.008. PMID: 25206547

41. Korpachev V.G., Lysenkov S.P., Tel L.Z. Modeling clinical death and postresuscitation disease in rats. Patologicheskaya Fiziologiya i Eksperimentalnaya Terapiya. 1982; 3: 78-80. PMID: 7122145. [In Russ.]

42. Avrushchenko M.Sh., Samorukova V.V., Moroz V.V., Volkov A.V., Nazarenko I.V., Gorenkova N.A. Development of postresuscitation mor- phological changes of hippocampal and cerebellar neurons: common reg- ularities and specific features. Patologicheskaya Fiziologiya i Eksperimentalnaya Terapiya. 2003; 2: 27-30. PMID: 12838772. [In Russ.] 4

43. ee T.H., Yang J.T., Ko Y.S., Kato H., Itoyama Y., Kogure K. Influence of ischemic preconditioning on levels of nerve growth factor, brain- derived neurotrophic factor and their high-affinity receptors in hip- pocampus following forebrain ischemia. Brain Res. 2008; 1187: 1-11. DOI: 10.1016/j.brainres.2007.09.078. PMID: 18036511

44. Mokhtari T., Akbari M., Malek F., Kashani I.R., Rastegar T., Noorbakhsh F., GhaziKhansari M., Attari F., Hassanzadeh G. Improvement of mem- ory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru. 2017; 25 (1): 4. DOI: 10.1186/s40199-017-0169-x. PMID: 28202057

45. Impellizzeri D., Campolo M., Bruschetta G., Crupi R., Cordaro M., Paterniti I., Cuzzocrea S., Esposito E. Traumatic brain injury leads to development of Parkinson’s disease related pathology in mice. Front. Neurosci. 2016; 10: 458. DOI: 10.3389/fnins.2016.00458. PMID: 27790086

46. Chen A.I., Xiong L.J., Tong Y.U., Mao M. The neuroprotective roles of BDNF in hypoxic ischemic brain injury. Biomed. Rep. 2013; 1 (2): 167- 176. DOI: 10.3892/br.2012.48. PMID: 24648914

47. Ploughman M., Windle V., MacLellan C.L., White N., Doré J.J., Corbett D. Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke. 2009; 40 (4): 1490-1495. DOI: 10.1161/STROKEAHA.108.531806. PMID: 19164786

48. Kiprianova I., Freiman T.M., Desiderato S., Schwab S., Galmbacher R., Gillardon F., Spranger M. Brain-derived neurotrophic factor prevents neuronal death and glial activation after global ischemia in the rat. J. Neurosci. Res. 1999; 56 (1): 21-27. DOI: 10.1002/(SICI)1097- 4547(19990401)56:1<21::AID-JNR3>3.0.CO;2-Q. PMID: 10213471

49. Zhang Y., Pardridge W.M. Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Res. 2006; 1111 (1): 227-229. DOI: PMID: 16884698

50. D’Cruz B.J., Fertig K.C., Filiano A.J., Hicks S.D., DeFranco D.B., Callaway C.W. Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. J. Cereb. Blood Flow Metab. 2002; 22 (7): 843-851. DOI: 10.1097/00004647-200207000- 00009. PMID: 12142569

51. Ostrowski R.P., Graupner G., Titova E., Zhang J., Chiu J., Dach N., Corleone D., Tang J., Zhang J.H. The hyperbaric oxygen precondition- ing-induced brain is mediated by a reduction of early apoptosis after transient cerebral ischemia Neurobiol. Dis. 2008; 29 (1): 1–13. DOI: 10.1016/j.nbd.2007.07.020. PMID: 17822911

52. shrat T., Sayeed I., Atif F., Hua F., Stein D.G. Progesterone is neuro- protective against ischemic brain injury through its effects on the PI3K/Akt signaling pathway. Neuroscience. 2012; 210: 442–450. DOI: 10.1016/j.neuroscience.2012.03.008. PMID: 22450229

53. Singh M., Su C. Progesterone-induced neuroprotection: factors that may predict therapeutic efficacy. Brain Res. 2013; 1514: 98-106. DOI: 10.1016/j.brainres.2013.01.027. PMID: 23340161

54. Li J., Ding X., Zhang R., Jiang W., Sun X., Xia Z., Wang X., Wu E., Zhang Y., Hu Y. Harpagoside ameliorates the amyloid-в-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3K pathways. Neuroscience. 2015; 303: 103-114. DOI: 10.1016/j.neuroscience.2015.06.042. PMID: 26135675

55. Liang C., Tan S., Huang Q., Lin J., Lu Z., Lin X. Pratensein ameliorates в-amyloid-induced cognitive impairment in rats via reducing oxidative damage and restoring synapse and BDNF levels. Neurosci. Lett. 2015; 592: 48-53. DOI: 0.1016/j.neulet.2015.03.003. PMID: 25748315

56. Fahimi A., Baktir M.A., Moghadam S., Mojabi F.S., Sumanth K., McNerney M.W., Ponnusamy R., Salehi A. Physical exercise induces structural alterations in the hippocampal astrocytes: exploring the role of BDNF-TrkB signaling. Brain Struct. Funct. 2017; 222 (4): 1797- 1808. DOI: 10.1007/s00429-016-1308-8. PMID: 27686571

57. Kim G., Kim E. The effects of antecedent exercise on motor function recovery and brain-derived neurotrophic factor expression after focal cerebral ischemia in rats. J. Phys. Ther. Sci. 2013; 25 (5): 553–556. DOI: 10.1589/jpts.25.553. PMID: 24259800

58. Shih P.C., Yang Y.R., Wang R.Y. Effects of exercise intensity on spatial memory performance and hippocampal synaptic plasticity in transient brain ischemic rats. PLoS One. 2013; 8 (10): e78163. DOI: 10.1371/journal.pone.0078163. PMID: 24205142

59. Seeds P., Leng Y., ChaleckaFranaszek E., Chuang D.M. Neurotrophinsprotect against cytosine arabinoside-induced apoptosis of immature rat cerebellar neurons. Neurochem. Int. 2005; 46 (1): 61–72. DOI: 10.1016/j.neuint.2004.07.001. PMID: 15567516

60. Géral C., Angelova A., Lesieur S. From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF). Pharmaceutics. 2013; 5 (1): 127-167. DOI: 10.3390/pharmaceutics5010127. PMID: 24300402

61. Huang L., Applegate P.M., Gatling J.W., Mangus D.B., Zhang J., Applegate R.L.2nd. A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (part II-comprehensive pro- tection). Med. Gas. Res. 2014; 4: 10. DOI: 10.1186/2045-9912-4-10. PMID: 25671079

62. Kim D.H., Zhao X., Tu C.H., CasacciaBonnefil P., Chao M.V. Prevention of apoptotic but not necrotic cell death following neuronal injury by neurotrophins signaling through the tyrosine kinase recep- tor. J. Neurosurg. 2004; 100 (1): 79-87. DOI: 10.3171/jns.2004. 100.1.0079. PMID: 14743916

63. Liu Z., Ma D., Feng G., Ma Y., Hu H. Recombinant AAV-mediated expression of human BDNF protects neurons against cell apoptosis in Abeta-induced neuronal damage model. J. Huazhong Univ. Sci. Technolog. Med. Sci. 2007; 27 (3): 233-236. DOI: 10.1007/s11596-007- 0304-x. PMID: 17641830

64. Takeshima Y., Nakamura M., Miyake H., Tamaki R., Inui T., Horiuchi K., Wajima D., Nakase H. Neuroprotection with intraventricular brain- derived neurotrophic factor in rat venous occlusion model. Neurosurgery. 2011; 68 (5): 1334-1341. DOI: 10.1227/NEU.0b013e 31820c048e. PMID: 21307800

65. Kazim S.F., Iqbal K. Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer’s disease. Mol. Neurodegener. 2016; 11 (1): 50. DOI: 10.1186/s13024-016-0119-y. PMID: 27400746

66. Khalin I., Alyautdin R., Kocherga G., Bakar M.A. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness. Int. J. Nanomedicine. 2015; 10: 3245-3267. DOI: 10.2147/IJN. S77480. PMID: 25995632

67. Pardridge W.M. Drug transport across the blood-brain barrier J. Cereb. Blood Flow Metab. 2012; 32 (11): 1959-1972. DOI: 10.1038/jcbfm.2012.126. PMID: 22929442

68. Alyautdin R., Khalin I., Nafeeza M.I., Haron M.H., Kuznetsov D. Nanoscale drug delivery systems and the blood-brain barrier. Int. J. Nanomedicine. 2014; 9: 795-811. DOI: 10.2147/IJN.S52236. PMID: 24550672

69. Shi Q., Zhang P., Zhang J., Chen X., Lu H., Tian Y., Parker T.L., Liu Y. 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.2009.08.049. PMID: 19703519

70. Liu X., Zhu Z., Kalyani M., Janik J.M., Shi H. Effects of energy status and diet on Bdnf expression in the ventromedial hypothalamus of male and female rats. Physiol. Behav. 2014; 130: 99-107. DOI: 10.1016/j.phys- beh.2014.03.028. PMID: 24709620

71. Gudasheva T.A., Povarnina P.Y., Seredenin S.B. Dipeptide mimetic of the brain-derived neurotrophic factor prevents impairments of neurogene- sis in stressed mice. Byulleten Experimentalnoi Biologii i Meditsiny. 2017; 162 (4): 454-457. DOI: 10.1007/s10517-017-3638-9. PMID: 28243910

72. Gudasheva T.A., Povarnina P.Y., Logvinov I.O., Antipova T.A., Seredenin S.B. Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats. Drug Des. Devel. Ther. 2016; 10: 3545-3553. DOI: 10.2147/DDDT.S118768. PMID: 27843294

73. Chen X., Wang K. The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995-2015. Acta Pharm. Sin. B. 2016; 6 (6): 522-530. DOI: 10.1016/j.apsb.2016.06.013. PMID: 27818918

74. Zhao H., Alam A., San C.Y., Eguchi S., Chen Q., Lian Q., Ma D. Molecular mechanisms of brain-derived neurotrophic factor in neuro- protection: recent developments. Brain Res. 2017; 1665: 1-21. DOI: 10.1016/j.brainres.2017.03.029. PMID: 28396009

75. Wang J., Zhang S., Ma H., Yang S., Liu Z., Wu X., Wang S., Zhang Y., Liu Y. Chronic intermittent hypobaric hypoxia pretreatment ameliorates ischemia-induced cognitive dysfunction through activation of ERK1/2-CREB-BDNF pathway in anesthetized mice. Neurochem. Res. 2017; 42 (2): 501-512. DOI: 10.1007/s11064-016-2097-4. PMID: 27822668

76. Shin M.K., Kim H.G., Kim K.L. A novel brain-derived neurotrophic fac- tor-modulating peptide attenuates Aв1-42-induced neurotoxicity in vitro. Neurosci. Lett. 2015; 595: 63-68. DOI: 10.1016/j.neulet.2015. 03.070. PMID: 25849526

77. Yang L., Jiang Y., Wen Z., Xu X., Xu X., Zhu J., Xie X., Xu L., Xie Y., Liu X., Xu G. Over-expressed EGR1 may exaggerate ischemic injury after exper- imental stroke by decreasing BDNF expression. Neuroscience. 2015; 290: 509-517. DOI: 10.1016/j.neuroscience.2015.01.020. PMID: 25637490

78. Patz S., Wahle P. Neurotrophins induce short-term and long-term changes of cortical neurotrophin expression. Eur. J. Neurosci. 2004; 20 (3): 701-708. DOI: 10.1111/j.1460-9568.2004.03519.x. PMID: 15255980

79. Kuo L.T., Groves M.J., Scaravilli F., Sugden D., An S.F. Neurotrophin-3 administration alters neurotrophin, neurotrophin receptor and nestin mRNA expression in rat dorsal root ganglia following axotomy. Neuroscience. 2007; 147 (2): 491-507. DOI: 10.1016/j.neuro- science.2007.04.023. PMID: 17532148

80. Rosso P., De Nicolò S., Carito V., Fiore M., Iannitelli A., Moreno S., Tirassa P. Ocular nerve growth factor administration modulates brain- derived neurotrophic factor signaling in prefrontal cortex of healthy and diabetic rats. CNS Neurosci. Ther. 2017; 23 (3): 198-208. DOI: 10.1111/cns.12661. PMID: 28044424

81. Avrushchenko M.Sh., Ostrova I.V., Zarzhetsky Yu.V., Moroz V.V., Gudasheva T.A., Seredenin S.B. Effect of the nerve growth factor mimetic GK-2 on post-resuscitation expression of neurotrophic fac- tors. Patologicheskaya Fiziologiya i Eksperimentalnaya Terapiya. 2015; 59 (2): 12-18. PMID: 26571801. [In Russ.]