РОЛЬ НЕЙРОТРОФИЧЕСКИХ ФАКТОРОВ ПЛАЦЕНТЫ В РАЗВИТИИ МОЗГА ПЛОДА ПРИ ГИПЕРГОМОЦИСТЕИНЕМИИ

DOI: https://doi.org/10.29296/24999490-2019-03-01

А.В. Арутюнян(1), доктор биологических наук, профессор, Ю.П. Милютина(1), кандидат биологических наук, И.В. Залозняя(1), кандидат биологических наук, А.Д. Щербицкая(2), Г.О. Керкешко(1), кандидат биологических наук 1-ФГБНУ «НИИ акушерства, гинекологии и репродуктологии им. Д.О. Отта», Российская Федерация, 199034, Санкт-Петербург, Менделеевская линия, д. 3; 2-ФГБУН «Институт эволюционной биохимии и физиологии им. И.М. Сеченова» РАН, Российская Федерация, 194223, Санкт-Петербург, проспект Тореза, д. 44 Е-mail: alexarutiunjan@gmail.com

В обзоре рассмотрены современные представления о роли нейротрофических факторов (BDNF, NGF, NRG1 и др.) в формировании плаценты и об их влиянии на развитие нервной системы плода в раннем онтогенезе. Приводятся данные о совместном действии нейротрофических факторов с фактором роста эндотелия сосудов и металлопротеиназами на процессы ангиогенеза в плаценте и мозге плода. Обсуждаются вопросы, связанные с влиянием провоспалительных цитокинов и оксилительного стресса на экспрессию нейротрофинов в плаценте, а также на развитие мозга у потомства. Проапоптотический эффект гомоцистеина на клетки трофобласта связан с развитием окислительного стресса, в то время как экспрессируемые в плаценте нейротрофины оказывают антиапоптотическое действие. Показано, что именно окислительный стресс имеет важнейшее значение в появлении долгосрочных нарушений развития нервной системы и когнитивной функции у потомства при гипергомоцистеинемии. Гипергомоцистеинемия также вызывает повышение в мозге уровня белка DYRK1A, в зрелом мозге сопровождающееся нейродегенерацией и снижением содержания BDNF, а у плодов – нарушениями развития мозга, приводящими к когнитивным нарушениям у потомства. Молекулярные механизмы воздействия пренатальной гипергомоцистеинемии на уровень нейротрофинов и их предшественников в плаценте и мозге плодов не представляются окончательно ясными и нуждаются в дальнейшем изучении.
Ключевые слова: 
плацента, плод

Список литературы: 
  1. Klein R., Smeyne R.J., Wurst W., Long L.K., Auerbach B.A., Joyner A.L., Barbacid M. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell. 1993; 75 (1): 113–22. https://doi.org/10.1016/S0092-8674(05)80088-1
  2. 2. Dhobale M.V., Pisal H.R., Mehendale S.S., Joshi S.R. Differential expression of human placental neurotrophic factors in preterm and term deliveries. Int. J. Dev. Neurosci. 2013; 31 (8): 719–23. https://doi.org/10.1016/j.ijdevneu.2013.09.006
  3. 3. Garces M.F., Sanchez E., Torres-Sierra A.L., Ruiz-Parra A.I., Angel-Muller E., Alzate J.P., Sanchez A.Y., Gomez M.A., Romero X.C., Castaneda Z.E., Sanchez-Rebordelo E., Dieguez C., Nogueiras R., Caminos J.E. Brain-derived neurotrophic factor is expressed in rat and human placenta and its serum levels are similarly regulated throughout pregnancy in both species. Clin. Endocrinol. (Oxf.). 2014; 81 (1): 141–51. https://doi.org/10.1111/cen.12391
  4. 4. Tometten M., Blois S., Arck P.C. Nerve growth factor in reproductive biology: link between the immune, endocrine and nervous system? Chem. Immunol. Allergy. 2005; 89: 135–48. https://doi.org/10.1159/000087962
  5. 5. Mayeur S., Lukaszewski M.A., Breton C., Storme L., Vieau D., Lesage J. Do neurotrophins regulate the feto-placental development? Med. Hypotheses. 2011; 76 (5): 726–8. https://doi.org/10.1016/j.mehy.2011.02.008
  6. 6. Dhobale M. Neurotrophins: Role in adverse pregnancy outcome. Int. J. Dev. Neurosci. 2014; 37: 8–14. https://doi.org/10.1016/j.ijdevneu.2014.06.005
  7. 7. Meeker R., Williams K. Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J. Neuroimmune Pharmacol. 2014; 9 (5): 615–28. https://doi.org/10.1007/s11481-014-9566-9
  8. 8. Teng K.K., Felice S., Kim T., Hempstead B.L. Understanding proneurotrophin actions: Recent advances and challenges. Dev. Neurobiol. 2010; 70 (5): 350–9. https://doi.org/10.1002/dneu.20768
  9. 9. 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): 737–44. https://doi.org/10.1016/j.placenta.2011.07.001
  10. 10. Kawamura K., Kawamura N., Kumazawa Y., Kumagai J., Fujimoto T., Tanaka T. Brain-derived neurotrophic factor/tyrosine kinase B signaling regulates human trophoblast growth in an in vivo animal model of ectopic pregnancy. Endocrinology. 2011; 152 (3): 1090–100. https://doi.org/10.1210/en.2010-1124
  11. 11. Kawamura K., Kawamura N., Sato W., Fukuda J., Kumagai J., Tanaka T. Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival. Endocrinology. 2009; 150 (8): 3774–82. https://doi.org/10.1210/en.2009-0213
  12. 12. Mayeur S., Silhol M., Moitrot E., Barbaux S., Breton C., Gabory A., Vaiman D., Dutriez-Casteloot I., Fajardy I., Vambergue A., Tapia-Arancibia L., Bastide B., Storme L., Junien C., Vieau D., Lesage J. Placental BDNF/TrkB signaling system is modulated by fetal growth disturbances in rat and human. Placenta. 2010; 31 (9): 785–91. https://doi.org/10.1016/j.placenta.2010.06.008
  13. 13. Sahay A.S., Sundrani D.P., Wagh G.N., Mehendale S.S., Joshi S.R. Neurotrophin levels in different regions of the placenta and their association with birth outcome and blood pressure. Placenta. 2015; 36 (8): 938–43. https://doi.org/10.1016/j.placenta.2015.06.006
  14. 14. Toti P., Ciarmela P., Florio P., Volpi N., Occhini R., Petraglia F. Human placenta and fetal membranes express nerve growth factor mRNA and protein. J. Endocrinol. Invest. 2006; 29 (4): 337–41. https://doi.org/10.1007/BF03344105
  15. 15. Sahay A.S., Sundrani D.P., Joshi S.R. Neurotrophins: role in placental growth and development. Vitam. Horm. 2017; 104: 243–61. https://doi.org/10.1016/bs.vh.2016.11.002
  16. 16. Lazarovici P., Marcinkiewicz C., Lelkes P.I. Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF)-implications in drug development. Curr. Pharm. Des. 2006; 12 (21): 2609–22. https://doi.org/10.2174/138161206777698738
  17. 17. Oosterbaan A.M., Steegers E.A., Ursem N.T. The effects of homocysteine and folic acid on angiogenesis and VEGF expression during chicken vascular development. Microvasc. Res. 2012; 83 (2): 98–104. https://doi.org/10.1016/j.mvr.2011.11.001
  18. 18. Xu X., Yang X.Y., He B.W., Yang W.J., Cheng W.W. Placental NRP1 and VEGF expression in pre-eclamptic women and in a homocysteine-treated mouse model of pre-eclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 2016; 196: 69–75. https://doi.org/10.1016/j.ejogrb.2015.11.017
  19. 19. Dammann O., Bueter W., Leviton A., Gressens P., Dammann C.E. Neuregulin-1: a potential endogenous protector in perinatal brain white matter damage. Neonatology. 2008; 93 (3): 182–7. https://doi.org/10.1159/000111119
  20. 20. Esper R.M., Pankonin M.S., Loeb J.A. Neuregulins: versatile growth and differentiation factors in nervous system development and human disease. Brain Res. Rev. 2006; 51 (2): 161–75. https://doi.org/10.1016/j.brainresrev.2005.11.006
  21. 21. Hoffmann I., Bueter W., Zscheppang K., Brinkhaus M.J., Liese A., Riemke S., Dork T., Dammann O., Dammann C.E. Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns. Brain Behav. Immun. 2010; 24 (5): 784–91. https://doi.org/10.1016/j.bbi.2009.08.012
  22. 22. Akbalik M.E., Ketani M.A. Expression of epidermal growth factor receptors and epidermal growth factor, amphiregulin and neuregulin in bovine uteroplacental tissues during gestation. Placenta. 2013; 34 (12): 1232–42. https://doi.org/10.1016/j.placenta.2013.09.019
  23. 23. Fock V., Plessl K., Draxler P., Otti G.R., Fiala C., Knofler M., Pollheimer J. Neuregulin-1-mediated ErbB2-ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation. J. Cell Sci. 2015; 128 (23): 4306–16. https://doi.org/10.1242/jcs.176933
  24. 24. Bilbo S.D., Schwarz J.M. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front. Behav. Neurosci. 2009; 3: 14. https://doi.org/10.3389/neuro.08.014.2009
  25. 25. Hsiao E.Y., Patterson P.H. Placental regulation of maternal-fetal interactions and brain development. Dev. Neurobiol. 2012; 72 (10): 1317–26. https://doi.org/10.1002/dneu.22045
  26. 26. Smith S.E., Li J., Garbett K., Mirnics K., Patterson P.H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 2007; 27 (40): 10695–702. https://doi.org/10.1523/JNEUROSCI.2178-07.2007
  27. 27. Gilmore J.H., Jarskog L.F., Vadlamudi S. Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal-fetal unit of the rat. J. Neuroimmunol. 2003; 138 (1-2): 49–55. https://doi.org/10.1016/S0165-5728(03)00095-X
  28. 28. Gilmore J.H., Jarskog L.F., Vadlamudi S. Maternal poly I:C exposure during pregnancy regulates TNF alpha, BDNF, and NGF expression in neonatal brain and the maternal-fetal unit of the rat. J. Neuroimmunol. 2005; 159 (1–2): 106–12. https://doi.org/10.1016/j.jneuroim.2004.10.008
  29. 29. Barrientos R.M., Sprunger D.B., Campeau S., Watkins L.R., Rudy J.W., Maier S.F. BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. J. Neuroimmunol. 2004; 155 (1–2): 119–26. https://doi.org/10.1016/j.jneuroim.2004.06.009
  30. 30. Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W. Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging. 2008; 29 (9): 1380–93. https://doi.org/10.1016/j.neurobiolaging.2007.02.027
  31. 31. Dhobale M., Mehendale S., Pisal H., Nimbargi V., Joshi S. Reduced maternal and cord nerve growth factor levels in preterm deliveries. Int. J. Dev. Neurosci. 2012; 30 (2): 99–103. https://doi.org/10.1016/j.ijdevneu.2011.12.007
  32. 32. Arutjunyan A., Kozina L., Stvolinskiy S., Bulygina Y., Mashkina A., Khavinson V. Pinealon protects the rat offspring from prenatal hyperhomocysteinemia. Int. J. Clin. Exp. Med. 2012; 5 (2): 179–85. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/
  33. 33. Baydas G., Koz S.T., Tuzcu M., Nedzvetsky V.S. Melatonin prevents gestational hyperhomocysteinemia-associated alterations in neurobehavioral developments in rats. J. Pineal Res. 2008; 44 (2): 181–8. https://doi.org/10.1111/j.1600-079X.2007.00506.x
  34. 34. Baydas G., Koz S.T., Tuzcu M., Nedzvetsky V.S., Etem E. Effects of maternal hyperhomocysteinemia induced by high methionine diet on the learning and memory performance in offspring. Int. J. Dev. Neurosci. 2007; 25 (3): 133–9. https://doi.org/10.1016/j.ijdevneu.2007.03.001
  35. 35. Gerasimova E., Yakovleva O., Burkhanova G., Khaertdinov N., Sitdikova G., Ziyatdinova G. Effects of maternal hyperhomocysteinemia on the early physical development and neurobehavioral maturation of rat offspring. BioNanoScience. 2017; 7 (1): 155–8. https://doi.org/10.1007/s12668-016-0326-6
  36. 36. Makhro A.V., Mashkina A.P., Solenaya O.A., Trunova O.A., Kozina L.S., Arutyunian A.V., Bulygina E.R. Prenatal hyperhomocysteinemia as a model of oxidative stress of the brain. Bull. Exp. Biol. Med. 2008; 146 (1): 33–5. https://doi.org/10.1007/s10517-008-0233-0
  37. 37. Махро А.В., Машкина А.П., Соленая О.А., Трунова О.А., Тюлина О.В., Булыгина Е.Р., Болдырев А.А. Карнозин защищает от окислительного стресса, вызванного гипергомоцистеинемией. Нейрохимия. 2008; 2 (3): 202–8. [Makhro A.V., Mashkina A.P., Solenaya O.A., Trunova O. A., Tyulina O.V., Bulygina E.R., Boldyrev A.A. Carnosine protects cells from oxidative stress induced by hyperhomocysteinemia. Nejrohimiya. 2008; 2 (3): 202–8 (in Russian)]
  38. 38. Griffiths R., Grieve A., Allen S., Olverman H.J. Neuronal and glial plasma membrane carrier-mediated uptake of L-homocysteate is not selectively blocked by beta-p-chlorophenylglutamate. Neurosci. Lett. 1992; 147 (2): 175–8. https://doi.org/10.1016/0304-3940(92)90588-X
  39. 39. Арутюнян А.В., Козина Л.С., Арутюнов В.А. Токсическое влияние пренатальной гипергомоцистеинемии на потомство (экспериментальное исследование). Журнал акушерства и женских болезней. 2010; 59 (4): 16–23. [Arutjunyan A.V., Kozina L.S., Arutyonov V.A. Toxic effect of prenatal hyperhomocysteinemia on offspring (experimental study). Z. Akus. Zen. Bolezn. 2010; 59 (4): 16–23 (in Russian)]
  40. 40. Арутюнян А.В., Пустыгина А.В., Милютина Ю.П., Залозняя И.В., Козина Л.С. Молекулярные маркеры окислительного стресса у потомства при экспериментальной гипергомоцистеинемии. Молекулярная медицина. 2015; 5: 41–6. [Arutjunyan A.V., Pustygina A.V., Milyutina Yu.P., Zaloznyaya I.V., Kozina L.S. Prenatal hyperhomocysteinemia and oxidative stress profile in the rat offspring. Molekulyarnaya meditsina. 2015; 5: 41–6 (in Russian)]
  41. 41. Пустыгина А.В., Милютина Ю.П., Залозняя И.В., Арутюнян А.В. Показатели окислительного стресса в мозге новорожденных крысят, перенесших пренатальную гипергомоцистеинемию. Нейрохимия. 2015; 32 (1): 71–7. [Pustygina A.V., Milyutina Yu.P., Zaloznyaya I.V., Arutyunyan A.V. Indices of oxidative stress in the brain of newborn rats subjected to prenatal hyperhomocystinemia. Nejrohimiya. 2015; 32(1): 71–7. https://doi.org/10.7868/S1027813315010070 (in Russian)]
  42. 42. Khavinson V., Ribakova Y., Kulebiakin K., Vladychenskaya E., Kozina L., Arutjunyan A., Boldyrev A. Pinealon increases cell viability by suppression of free radical levels and activating proliferative processes. Rejuvenation Res. 2011; 14 (5): 535–41. https://doi.org/10.1089/rej.2011.1172
  43. 43. Sable P., Kale A., Joshi A., Joshi S. Maternal micronutrient imbalance alters gene expression of BDNF, NGF, TrkB and CREB in the offspring brain at an adult age. Int. J. Dev. Neurosci. 2014; 34: 24–32. https://doi.org/10.1016/j.ijdevneu.2014.01.003
  44. 44. Di Simone N., Maggiano N., Caliandro D., Riccardi P., Evangelista A., Carducci B., Caruso A. Homocysteine induces trophoblast cell death with apoptotic features. Biol. Reprod. 2003; 69 (4): 1129–34. https://doi.org/10.1095/biolreprod.103.015800
  45. 45. Kamudhamas A., Pang L., Smith S.D., Sadovsky Y., Nelson D.M. Homocysteine thiolactone induces apoptosis in cultured human trophoblasts: a mechanism for homocysteine-mediated placental dysfunction? Am. J. Obstet. Gynecol. 2004; 191 (2): 563–71. https://doi.org/10.1016/j.ajog.2004.01.037
  46. 46. Koz S.T., Gouwy N.T., Demir N., Nedzvetsky V.S., Etem E., Baydas G. Effects of maternal hyperhomocysteinemia induced by methionine intake on oxidative stress and apoptosis in pup rat brain. Int. J. Dev. Neurosci. 2010; 28 (4): 325–9. https://doi.org/10.1016/j.ijdevneu.2010.02.006
  47. 47. Di Simone N., Riccardi P., Maggiano N., Piacentani A., D’Asta M., Capelli A., Caruso A. Effect of folic acid on homocysteine-induced trophoblast apoptosis. Mol. Hum. Reprod. 2004; 10 (9): 665–9. https://doi.org/10.1093/molehr/gah091
  48. 48. Suhara T., Fukuo K., Yasuda O., Tsubakimoto M., Takemura Y., Kawamoto H., Yokoi T., Mogi M., Kaimoto T., Ogihara T. Homocysteine enhances endothelial apoptosis via upregulation of Fas-mediated pathways. Hypertension. 2004; 43 (6): 1208–13. https://doi.org/10.1161/01.HYP.0000127914.94292.76
  49. 49. Cai B., Li X., Wang Y., Liu Y., Yang F., Chen H., Yin K., Tan X., Zhu J., Pan Z., Wang B., Lu Y. Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal. PLoS One. 2013; 8 (5): e63561. https://doi.org/10.1371/journal.pone.0063561
  50. 50. Lanoix D., Lacasse A.A., Reiter R.J., Vaillancourt C. Melatonin: the smart killer: the human trophoblast as a model. Mol. Cell. Endocrinol. 2012; 348 (1): 1–11. https://doi.org/10.1016/j.mce.2011.08.025
  51. 51. Stagni F., Giacomini A., Emili M., Guidi S., Bartesaghi R. Neurogenesis impairment: An early developmental defect in Down syndrome. Free Radic. Biol. Med 2018; 114: 15–32. https://doi.org/10.1016/j.freeradbiomed.2017.07.026
  52. 52. Nakano-Kobayashi A., Awaya T., Kii I., Sumida Y., Okuno Y., Yoshida S., Sumida T., Inoue H., Hosoya T., Hagiwara M. Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. Proc. Natl. Acad. Sci. U.S.A. 2017; 114 (38): 10268–73. https://doi.org/10.1073/pnas.1704143114
  53. 53. Baloula V., Fructuoso M., Kassis N., Gueddouri D., Paul J.L., Janel N. Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia. Redox Biol. 2018; 19: 200–9. https://doi.org/10.1016/j.redox.2018.08.015
  54. 54. Janel N., Alexopoulos P., Badel A., Lamari F., Camproux A.C., Lagarde J., Simon S., Feraudet-Tarisse C., Lamourette P., Arbones M., Paul J.L., Dubois B., Potier M.C., Sarazin M., Delabar J.M. Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer’s disease. Transl. Psychiatry. 2017; 7 (6): e1154. https://doi.org/10.1038/tp.2017.123
  55. 55. Souchet B., Latour A., Gu Y., Daubigney F., Paul J.L., Delabar J.M., Janel N. Molecular rescue of DYRK1A overexpression in cystathionine beta synthase-deficient mouse brain by enriched environment combined with voluntary exercise. J. Mol. Neurosci. 2015; 55 (2): 318–23. https://doi.org/10.1007/s12031-014-0324-5
  56. 56. Deinhardt K., Chao M.V. Shaping neurons: Long and short range effects of mature and proBDNF signalling upon neuronal structure. Neuropharmacology. 2014; 76: 603–9. https://doi.org/10.1016/j.neuropharm.2013.04.054
  57. 57. Woo N.H., Teng H.K., Siao C.J., Chiaruttini C., Pang P.T., Milner T.A., Hempstead B.L., Lu B. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci. 2005; 8 (8): 1069–77. https://doi.org/10.1038/nn1510
  58. 58. Yang J., Harte-Hargrove L.C., Siao C.J., Marinic T., Clarke R., Ma Q., Jing D., Lafrancois J.J., Bath K.G., Mark W., Ballon D., Lee F.S., Scharfman H.E., Hempstead B.L. ProBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep. 2014; 7 (3): 796–806. https://doi.org/10.1016/j.celrep.2014.03.040
  59. 59. Peng S., Wuu J., Mufson E.J., Fahnestock M. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J. Neuropathol. Exp. Neurol. 2004; 63 (6): 641–9. https://doi.org/10.1093/jnen/63.6.641
  60. 60. Tiveron C., Fasulo L., Capsoni S., Malerba F., Marinelli S., Paoletti F., Piccinin S., Scardigli R., Amato G., Brandi R., Capelli P., D’Aguanno S., Florenzano F., La Regina F., Lecci A., Manca A., Meli G., Pistillo L., Berretta N., Nistico R., Pavone F., Cattaneo A. ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice. Cell Death Differ. 2013; 20 (8): 1017–30. https://doi.org/10.1038/cdd.2013.22