The Role of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor in Chronic Fetal Oxygen Deprivation

The aim of the study was to define the role of brain-derived and glial cell line-derived neurotrophic factors (BDNF and GDNF) in realization of compensative and adaptive mechanisms of a neonatal organism to hypoxia.

Materials and Methods. The experiments in vivo have been carried out on pregnant C57BL/6 mice (n=36). Chronic hypobaric hypoxia has been modeled in different pregnancy trimesters. On gestation days E19–20, concentration of BDNF and GDNF in the blood of the pregnant females was determined by enzyme immunoassay. Further, the number of neonatal mice, their weight and body length parameters have been assessed.

Parturient mothers (n=88) and their newborn babies followed up at the Clinic of Obstetrics and Gynecology of Pavlov University took part in the clinical investigations. Concentration of BDNF, GDNF, neuron-specific enolase (NSE), and hypoxia-inducible factor (HIF-1β) in the fetal cord blood has been determined by ELISA. The obtained data were retrospectively compared with cardiotocography, dopplerometry, presence of meconium-stained amniotic fluid and the neonate state at birth, assessment according to the Apgar score, and the course of adaptation period.

Results. Chronic hypobaric hypoxia in pregnant mice in trimester I and II resulted in the significant decrease of BDNF and GDNF level, decrease in the number of embryos, and in significant changes in weight/height characteristics of the newborn pups.

According to the clinical observations, an increased expression of the neurotrophic factors BDNF, GDNF provides protection to a neonate even if hypoxia factors are present and realized. A low content of BDNF and GDNF was observed in the group of infants with a high risk of developing unfavorable hypoxic damaging effects.

Conclusion. The protective role of BDNF and GDNF in the regulation of fetal homeostasis in chronic hypoxia has been established experimentally and clinically.

1. Fedorova M.V. Diagnostika i lechenie vnutriutrobnoy gipoksii ploda [Diagnosis and treatment of fetal hypoxia]. Moscow: Meditsina; 1982; 207 p.
2. Hennigan A., O’Callaghan R.M., Kelly A.M. Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. Biochem Soc Trans 2007; 35(2): 424–427, https://doi.org/10.1042/bst0350424.
3. Fominova U.N., Gurina O.I., Shepeleva I.I., Popova T.N., Kekelidze Z.I., Chekhonin V.P. Brain-derived neurotrophic factor: structure and interaction with receptors. Rossiyskiy psikhiatricheskiy zhurnal 2018; 4: 64–72.
4. Urazov М.D., Astrakhanova Т.А., Usenko А.V., Mishchenko Т.А., Schelchkova N.А., Kravchenko G.A., Vedunova М.V., Mitroshina Е.V. New aspects of central nervous system adaptation to prenatal hypoxia. Sovremennye tehnologii v medicine 2018; 10(4): 60–68, https://doi.org/10.17691/stm2018.10.4.07.
5. Giannopoulou I., Pagida M.A., Briana D.D., Panayotacopoulou M.T. Perinatal hypoxia as a risk factor for psychopathology later in life: the role of dopamine and neurotrophins. Hormones 2018; 17(1): 25–32, https://doi.org/10.1007/s42000-018-0007-7.
6. Benarroch E.E. Brain-derived neurotrophic factor: regulation, effects, and potential clinical relevance. Neurology 2015; 84(16): 1693–1694, https://doi.org/10.1212/wnl.0000000000001507.
7. Kowiański P., Lietzau G., Czuba E., Waśkow M., Steliga A., Moryś J. BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol 2018; 38(3): 579–593, https://doi.org/10.1007/s10571-017-0510-4.
8. Mishchenko T.A., Mitroshina E.V., Usenko A.V., Voronova N.V., Astrakhanova T.A., Shirokova O.M., Kastalskiy I.A., Vedunova M.V. Features of neural network formation and their functions in primary hippocampal cultures on the background of chronic TrkB receptor system influence. Front Physiol 2019; 9: 1925, https://doi.org/10.3389/fphys.2018.01925.
9. Duarte E.P., Curcio M., Canzoniero L.M., Duarte C.B. Neuroprotection by GDNF in the ischemic brain. Growth Factors 2012; 30(4): 242–257, https://doi.org/10.3109/08977194.2012.691478.
10. Mitroshina Е.V., Mishchenko T.A., Shirokova O.M., Astrakhanova T.A., Loginova M.M., Epifanova E.A., Babaev A.A., Tarabykin V.S., Vedunova M.V. Intracellular neuroprotective mechanisms in neuron-glial networks mediated by glial cell line-derived neurotrophic factor. Oxid Med Cell Longev 2019; 2019: 1036907, https://doi.org/10.1155/2019/1036907.
11. Celtik C., Acunaş B., Oner N., Pala O. Neuron-specific enolase as a marker of the severity and outcome of hypoxic ischemic encephalopathy. Brain Dev 2004; 26(6): 398–402, https://doi.org/10.1016/j.braindev.2003.12.007.
12. Morozova A.Y., Milyutina Yu.P., Arutyunyan A.V., Evsyukova I.I. The contents of neurospecific enolase and neurotrofic growth factor in the cord blood of healthy full-term newborns elective planned caesarean section surgery and spontaneous delivery. Zhurnal akusherstva i zhenskikh bolezney 2015; 64(6): 38–42.
13. Chen R., Lai U.H., Zhu L., Singh A., Ahmed M., Forsyth N.R. Reactive oxygen species formation in the brain at different oxygen levels: the role of hypoxia inducible factors. Front Cell Dev Biol 2018; 6: 132, https://doi.org/10.3389/fcell.2018.00132.
14. Adachi N., Numakawa T., Richards M., Nakajima S., Kunugi H. New insight in expression, transport, and secretion of brain-derived neurotrophic factor: implications in brain-related diseases. World J Biol Chem 2014; 5(4): 409–428, https://doi.org/10.4331/wjbc.v5.i4.409.
15. Shishkina T.V., Mishchenko T.A., Mitroshina E.V., Pimashkin A.S., Kastalskiy I.A., Mukhina I.V., Kazantsev V.B., Vedunova M.V., Shirokova O.M. Glial cell line-derived neurotrophic factor (GDNF) counteracts hypoxic damage to hippocampal neural network function in vitro. Brain Res 2018; 1678: 310–321, https://doi.org/10.1016/j.brainres.2017.10.023.
16. Vedunova М.V., Sakharnova Т.А., Mitroshina E.V., Shishkina T.V., Astrakhanova T.A., Mukhina I.V. Antihypoxic and neuroprotective properties of BDNF and GDNF in vitro and in vivo under hypoxic conditions. Sovremennye tehnologii v medicine 2014; 6(4): 38–47.
17. Maragakis N.J., Rothstein J.D. Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2006; 2(12): 679–689, https://doi.org/10.1038/ncpneuro0355.
18. Capani F., Quarracino C., Caccuri R., Sica R.E. Astrocytes as the main players in primary degenerative disorders of the human central nervous system. Front Aging Neurosci 2016; 8: 45, https://doi.org/10.3389/fnagi.2016.00045.
19. Douglas-Escobar M., Weiss M.D. Biomarkers of hypoxic-ischemic encephalopathy in newborns. Front Neurol 2012; 3: 144, https://doi.org/10.3389/fneur.2012.00144.
20. Pan W., Banks W.A., Fasold M.B., Bluth J., Kastin A.J. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998; 37(12): 1553–1561, https://doi.org/10.1016/s0028-3908(98)00141-5.
21. Karege F., Schwald M., Cisse M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett 2002; 328(3): 261–264, https://doi.org/10.1016/s0304-3940(02)00529-3.
22. Fujita K., Tatsumi K., Kondoh E., Chigusa Y., Mogami H., Fujii T., Yura S., Kakui K., Konishi I. Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors. Placenta 2011; 32(10): 737–744, https://doi.org/10.1016/j.placenta.2011.07.001.
23. Sahay A.S., Sundrani D.P., Joshi S.R. Neurotrophins: role in placental growth and development. Vitam Horm 2017; 104: 243–261, https://doi.org/10.1016/bs.vh.2016.11.002.
24. Mayeur S., Lukaszewski M.A., Breton C., Storme L., Vieau D., Lesage J. Do neurotrophins regulate the feto-placental development? J Med Hypotheses 2011; 76(5): 726–728, https://doi.org/10.1016/j.mehy.2011.02.008.
25. Rajkumar R., Bhaya B., Mamilla D., Czech T., Kisseih E., Saini A., Chouthai N. A preliminary evaluation of glial cell line-derived neurotrophic factor (GDNF) levels in cerebrospinal fluid across various gestational ages and clinical conditions of the neonate. Int J Dev Neurosci 2018; 65: 61–65, https://doi.org/10.1016/j.ijdevneu.2017.10.001.
26. Kinjo T., Ohga S., Ochiai M., Honjo S., Tanaka T., Takahata Y., Ihara K., Hara T. Serum chemokine levels and developmental outcome in preterm infants. Early Human Development 2011; 87(6): 439–443, https://doi.org/10.1016/j.earlhumdev.2011.03.006.

Shchelchkova N.A., Kokaya A.A., Bezhenar’ V.F., Rozhdestvenskaya O.V., Mamedova M.A., Mishchenko T.A., Mitroshina E.V., Vedunova M.V. The Role of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor in Chronic Fetal Oxygen Deprivation. Sovremennye tehnologii v medicine 2020; 12(1): 25, https://doi.org/10.17691/stm2020.12.1.03