Влияние кортикостерона и антидепрессантов флуоксетин и амитриптилин на экспрессию нейротрофических факторов в клетках астроцитомы крысы линии C6

Авторы:

Новоженова А.Н.,

Долотов О.В.,

Гривенников И.А.

Журнал: Молекулярная генетика, микробиология и вирусология. 2025;43(4-2):111-120.

DOI: 10.17116/molgen202543042111

Прочитано: 1126 раз

Резюме

ВВЕДЕНИЕ

Депрессия является наиболее распространенным психическим заболеванием. Этиопатогенез депрессии и механизмы действия антидепрессантов недостаточно изучены. Накопленные данные указывают на вовлеченность нейротрофических факторов (НТФ) в развитие депрессии и эффекты антидепрессантов. Хронический стресс является фактором риска развития депрессии и приводит к снижению уровней НТФ в ряде отделов мозга. Практически не исследованы эффекты хронического воздействия глюкокортикоидов и антидепрессантов на экспрессию НТФ в астроцитах.

ЦЕЛЬ РАБОТЫ

Оценка влияния кортикостерона в стрессовой концентрации и антидепрессантов на экспрессию в клетках линии C6 вовлеченных в развитие депрессии НТФ.

МАТЕРИАЛ И МЕТОДЫ

Использовали клетки астроцитомы крысы линии C6. В бессывороточную культуральную среду вводили кортикостерон в базальной (0.1 мкМ) и стрессовой (1 мкМ) концентрациях, амитриптилин (25 мкМ) или флуоксетин (10 мкМ) однократно или в течение 7 дней. Через 24 ч оценивали уровни мРНК BDNF, NGF, VEGF и S100β с помощью ОТ-ПЦР в реальном времени.

РЕЗУЛЬТАТЫ

Кортикостерон (1 мкМ) стимулировал экспрессию BDNF при остром и хроническом воздействии, но снижал экспрессию NGF при остром и стимулировал при хроническом. Стимуляция экспрессии S100β и подавление экспрессии VEGF обнаружены только при хроническом воздействии. Антидепрессанты стимулировали экспрессию BDNF и NGF только при хроническом воздействии на фоне базальной концентрации кортикостерона. Антидепрессанты повышали экспрессию VEGF при хроническом воздействии на фоне обеих концентраций кортикостерона.

ЗАКЛЮЧЕНИЕ

Представленные данные показывают, что кортикостерон в стрессовой концентрации регулирует экспрессию в клетках C6 вовлеченных в развитие депрессии НТФ. Результаты работы указывают на нейропротекторную роль астроцитов при стрессе и могут быть использованы для разработки клеточных моделей, направленных на изучение механизмов влияния стресса на ЦНС и тестирования соединений с потенциальной антидепрессантной активностью.

Ключевые слова

стресс
глюкокортикоиды
кортикостерон
депрессия
антидепрессанты
астроциты
астроцитома крысы линии C6
нейротрофические факторы

Дата поступления: 03.10.2025

Дата принятия в печать: 23.10.2025

Дата публикации: 08.12.2025

Литература / References

Smith K. Mental health: a world of depression. Nature. 2014;515(7526):181. https://doi.org/10.1038/515180a
Kraus C, Kadriu B, Lanzenberger R, Zarate CA, Jr., Kasper S. Prognosis and improved outcomes in major depression: a review. Translational psychiatry. 2019;9(1):127. https://doi.org/10.1038/s41398-019-0460-3
Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatric services (Washington, DC). 2009;60(11):1439-45. https://doi.org/10.1176/ps.2009.60.11.1439
Zunszain PA, Anacker C, Cattaneo A, Carvalho LA, Pariante CM. Glucocorticoids, cytokines and brain abnormalities in depression. Progress in neuro-psychopharmacology & biological psychiatry. 2011;35(3):722-9. https://doi.org/10.1016/j.pnpbp.2010.04.011
De Kloet ER. Hormones and the stressed brain. Annals of the New York Academy of Sciences. 2004;1018:1-15. https://doi.org/10.1196/annals.1296.001
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Archives of general psychiatry. 1997;54(7):597-606. https://doi.org/10.1001/archpsyc.1997.01830190015002
Mondal AC, Fatima M. Direct and indirect evidences of BDNF and NGF as key modulators in depression: role of antidepressants treatment. The International journal of neuroscience. 2019;129(3):283-296. https://doi.org/10.1080/00207454.2018.1527328
Dolotov OV, Inozemtseva LS, Myasoedov NF, Grivennikov IA. Stress-Induced Depression and Alzheimer’s Disease: Focus on Astrocytes. International journal of molecular sciences. 2022;23(9). https://doi.org/10.3390/ijms23094999
Zhou X, Xiao Q, Xie L, Yang F, Wang L, Tu J. Astrocyte, a Promising Target for Mood Disorder Interventions. Frontiers in molecular neuroscience. 2019;12:136. https://doi.org/10.3389/fnmol.2019.00136
Gubba EM, Fawcett JW, Herbert J. The effects of corticosterone and dehydroepiandrosterone on neurotrophic factor mRNA expression in primary hippocampal and astrocyte cultures. Brain research Molecular brain research. 2004;127(1-2):48-59. https://doi.org/10.1016/j.molbrainres.2004.05.004
Kirby ED, Muroy SE, Sun WG, Covarrubias D, Leong MJ, Barchas LA, Kaufer D. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2. eLife. 2013;2:e00362. https://doi.org/10.7554/eLife.00362
Henkel AW, Alali H, Devassy A, Alawadi MM, Redzic ZB. Antagonistic interactions between dexamethasone and fluoxetine modulate morphodynamics and expression of cytokines in astrocytes. Neuroscience. 2014;280:318-27. https://doi.org/10.1016/j.neuroscience.2014.09.012
Machein MR, Kullmer J, Rönicke V, Machein U, Krieg M, Damert A, Breier G, Risau W, Plate KH. Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathology and applied neurobiology. 1999;25(2):104-12. https://doi.org/10.1046/j.1365-2990.1999.00166.x
Lowe WL, Jr., Meyer T, Karpen CW, Lorentzen LR. Regulation of insulin-like growth factor I production in rat C6 glioma cells: possible role as an autocrine/paracrine growth factor. Endocrinology. 1992;130(5):2683-91. https://doi.org/10.1210/endo.130.5.1572288
Verity AN, Wyatt TL, Hajos B, Eglen RM, Baecker PA, Johnson RM. Regulation of glial cell line-derived neurotrophic factor release from rat C6 glioblastoma cells. Journal of neurochemistry. 1998;70(2):531-9. https://doi.org/10.1046/j.1471-4159.1998.70020531.x
Galland F, Seady M, Taday J, Smaili SS, Gonçalves CA, Leite MC. Astrocyte culture models: Molecular and function characterization of primary culture, immortalized astrocytes and C6 glioma cells. Neurochemistry international. 2019;131:104538. https://doi.org/10.1016/j.neuint.2019.104538
Allaman I, Fiumelli H, Magistretti PJ, Martin JL. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology. 2011;216(1):75-84. https://doi.org/10.1007/s00213-011-2190-y
Kim Y, Kim SH, Kim YS, Lee YH, Ha K, Shin SY. Imipramine activates glial cell line-derived neurotrophic factor via early growth response gene 1 in astrocytes. Progress in neuro-psychopharmacology & biological psychiatry. 2011;35(4):1026-32. https://doi.org/10.1016/j.pnpbp.2011.02.012
Kittel-Schneider S, Kenis G, Schek J, van den Hove D, Prickaerts J, Lesch KP, Steinbusch H, Reif A. Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes. Frontiers in psychiatry. 2012;3:33. https://doi.org/10.3389/fpsyt.2012.00033
Hisaoka K, Nishida A, Koda T, Miyata M, Zensho H, Morinobu S, Ohta M, Yamawaki S. Antidepressant drug treatments induce glial cell line-derived neurotrophic factor (GDNF) synthesis and release in rat C6 glioblastoma cells. Journal of neurochemistry. 2001;79(1):25-34. https://doi.org/10.1046/j.1471-4159.2001.00531.x
Golan M, Schreiber G, Avissar S. Antidepressants elevate GDNF expression and release from C₆ glioma cells in a β-arrestin1-dependent, CREB interactive pathway. The international journal of neuropsychopharmacology. 2011;14(10):1289-300. https://doi.org/10.1017/s1461145710001550
Heard KJ, Shokhirev MN, Becronis C, Fredlender C, Zahid N, Le AT, Ji Y, Skime M, Nelson T, Hall-Flavin D, Weinshilboum R, Gage FH, Vadodaria KC. Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients. Translational psychiatry. 2021;11(1):608. https://doi.org/10.1038/s41398-021-01733-9
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif). 2001;25(4):402-8. https://doi.org/10.1006/meth.2001.1262
Vahl TP, Ulrich-Lai YM, Ostrander MM, Dolgas CM, Elfers EE, Seeley RJ, D’Alessio DA, Herman JP. Comparative analysis of ACTH and corticosterone sampling methods in rats. American journal of physiology Endocrinology and metabolism. 2005;289(5):E823-8. https://doi.org/10.1152/ajpendo.00122.2005
Bekhbat M, Glasper ER, Rowson SA, Kelly SD, Neigh GN. Measuring corticosterone concentrations over a physiological dynamic range in female rats. Physiology & behavior. 2018;194:73-76. https://doi.org/10.1016/j.physbeh.2018.04.033
Hisaoka-Nakashima K, Kajitani N, Kaneko M, Shigetou T, Kasai M, Matsumoto C, Yokoe T, Azuma H, Takebayashi M, Morioka N, Nakata Y. Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia. Brain research. 2016;1634:57-67. https://doi.org/10.1016/j.brainres.2015.12.057
Feoktistova M, Geserick P, Leverkus M. Crystal Violet Assay for Determining Viability of Cultured Cells. Cold Spring Harbor protocols. 2016;2016(4):pdb prot087379. https://doi.org/10.1101/pdb.prot087379
Wang J, Meng F, Wang L, Li Z. Vascular endothelial growth factor: a key factor in the onset and treatment of depression. Frontiers in cellular neuroscience. 2025;19:1645437. https://doi.org/10.3389/fncel.2025.1645437
Lang UE, Borgwardt S. Molecular mechanisms of depression: perspectives on new treatment strategies. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2013;31(6):761-77. https://doi.org/10.1159/000350094
Kroksmark H, Vinberg M. Does S100B have a potential role in affective disorders? A literature review. Nordic journal of psychiatry. 2018;72(7):462-470. https://doi.org/10.1080/08039488.2018.1472295
Rajkowska G, Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Current drug targets. 2013;14(11):1225-36. https://doi.org/10.2174/13894501113149990156
Fan XX, Sun WY, Li Y, Tang Q, Li LN, Yu X, Wang SY, Fan AR, Xu XQ, Chang HS. Honokiol improves depression-like behaviors in rats by HIF-1α- VEGF signaling pathway activation. Frontiers in pharmacology. 2022;13:968124. https://doi.org/10.3389/fphar.2022.968124
Barros RG, de Carvalho JNE, da Silva CP, Nishimura FG, Beleboni RO. Regulation of Cerebral BDNF, VEGF, and GluN2B Gene Expression and Cytokine Levels by Riparin A in a Murine Model of Depression. Advances in pharmacological and pharmaceutical sciences. 2025;2025:6965826. https://doi.org/10.1155/adpp/6965826
Rong H, Wang G, Liu T, Wang H, Wan Q, Weng S. Chronic mild stress induces fluoxetine-reversible decreases in hippocampal and cerebrospinal fluid levels of the neurotrophic factor S100B and its specific receptor. International journal of molecular sciences. 2010;11(12):5310-22. https://doi.org/10.3390/ijms11125310
Ye Y, Wang G, Wang H, Wang X. Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression. Neuroscience letters. 2011;503(1):15-9. https://doi.org/10.1016/j.neulet.2011.07.055
Brivio P, Sbrini G, Riva MA, Calabrese F. Acute Stress Induces Cognitive Improvement in the Novel Object Recognition Task by Transiently Modulating Bdnf in the Prefrontal Cortex of Male Rats. Cellular and molecular neurobiology. 2020;40(6):1037-1047. https://doi.org/10.1007/s10571-020-00793-7
Nowacka M, Obuchowicz E. BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies. Pharmacological reports : PR. 2013;65(3):535-46. https://doi.org/10.1016/s1734-1140(13)71031-4
Simões DM, Carreira J, Henriques A, Gaspar R, Sanches ES, Baptista FI, Silva AP. Distinct behavioural and neurovascular signatures induced by acute and chronic stress in rats. Behavioural brain research. 2025;493:115706. https://doi.org/10.1016/j.bbr.2025.115706
Park HJ, Lee S, Jung JW, Kim BC, Ryu JH, Kim DH. Glucocorticoid- and long-term stress-induced aberrant synaptic plasticity are mediated by activation of the glucocorticoid receptor. Archives of pharmacal research. 2015;38(6):1204-12. https://doi.org/10.1007/s12272-015-0548-0
Nitta A, Ohmiya M, Sometani A, Itoh M, Nomoto H, Furukawa Y, Furukawa S. Brain-derived neurotrophic factor prevents neuronal cell death induced by corticosterone. Journal of neuroscience research. 1999;57(2):227-35. https://doi.org/10.1002/(sici)1097-4547(19990715)57:2<227::aid-jnr8>3.0.co;2-e
Tsimpolis A, Kokkali M, Logothetis A, Kalafatakis K, Charalampopoulos I. Biphasic Response of Astrocytic Brain-Derived Neurotrophic Factor Expression following Corticosterone Stimulation. Biomolecules. 2022;12(9) https://doi.org/10.3390/biom12091322
Pshenichkin SP, Szekely AM, Wise BC. Transcriptional and posttranscriptional mechanisms involved in the interleukin-1, steroid, and protein kinase C regulation of nerve growth factor in cortical astrocytes. Journal of neurochemistry. 1994;63(2):419-28. https://doi.org/10.1046/j.1471-4159.1994.63020419.x
Niu H, Hinkle DA, Wise PM. Dexamethasone regulates basic fibroblast growth factor, nerve growth factor and S100beta expression in cultured hippocampal astrocytes. Brain research Molecular brain research. 1997;51(1-2):97-105. https://doi.org/10.1016/s0169-328x(97)00221-0