Abstract
Rationale
Antidepressants could exert neuroprotective effects against various insults and the antidepressant-like effect may result from its neuroprotective effects. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is a key signaling pathway in mediating cell survival. However, no information is available regarding the interaction of FoxO3a and antidepressants.
Objectives
PC12 cells treated with corticosterone were used as a model to study the protective effect of venlafaxine and underlying mechanisms.
Methods
Methyl thiazolyl tetrazolium (MTT) assay, Hoechst staining, and the observation of FoxO3a subcellular location were used to study the protective effect of venlafaxine against cell damage caused by corticosterone. Pretreatments with various pathway inhibitors were used to investigate the possible pathways involved in the protection of venlafaxine. The phosphorylation of Akt and FoxO3a was analyzed by Western blot.
Results
Corticosterone decreased the phosphorylation of Akt and FoxO3a and led to the nuclear localization of FoxO3a and the apoptosis of PC12 cells. Venlafaxine concentration-dependently protected PC12 cells against corticosterone. The protective effect of venlafaxine was reversed by LY294002 and wortmannin, two PI3K inhibitors, and Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MAPK kinase) inhibitor PD98059 and the p38 MAPK inhibitor PD160316 had no effect. Western blot analyses showed that venlafaxine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a, and the nuclear translocation of Foxo3a induced by corticosterone.
Conclusions
Venlafaxine protects PC12 cells against corticosterone-induced cell death by modulating the activity of the PI3K/Akt/FoxO3a pathway.
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References
Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117:421–426
Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH Jr, Krishnan KR (1993) Hypercortisolemia and hippocampal changes in depression. Psychiat Res 47:163–173
Bang OS, Park EK, Yang SI, Lee SR, Franke TF, Kang SS (2001) Overexpression of Akt inhibits NGF-induced growth arrest and neuronal differentiation of PC12 cells. J Cell Sci 114:81–88
Barden N (2004) Implication of the hypothalamic–pituitary–adrenal axis in the physiopathology of depression. J Psychiatry Neurosci 29:185–193
Bijak M, Zahorodna A, Tokarski K (2001) Opposite effects of antidepressants and corticosterone on the sensitivity of hippocampal CA1 neurons to 5-HT1A and 5-HT4 receptor activation. Naunyn Schmiedebergs Arch Pharmacol 363:491–498
Budni J, Romero A, Molz S, Martín-de-Saavedra MD, Egea J, Del Barrio L, Tasca CI, Rodrigues AL, López MG (2011) Neurotoxicity induced by dexamethasone in the human neuroblastoma SH-SY5Y cell line can be prevented by folic acid. Neuroscience 190:346–353
Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, Kolodziej P, Kahn I, Saftig P, Woulfe J, Rochet JC, Glicksman MA, Cheng SH, Grabowski GA, Shihabuddin LS, Schlossmacher MG (2011) Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol 69:940–953
Dixon JF, Hokin LE (1998) Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex. Proc Natl Acad Sci U S A 95:8363–8368
Guerry JD, Hastings PD (2011) In search of HPA axis dysregulation in child and adolescent depression. Clin Child Fam Psychol Rev 14:135–160
Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008) The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33:693–710
Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis. Trends Neurosci 20:78–84
Holsboer F (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 33:181–214
Johnson SA, Fournier NM, Kalynchuk LE (2006) Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res 168:280–288
Khawaja X, Xu J, Liang JJ, Barrett JE (2004) Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: implications for depressive disorders and future therapies. J Neurosci Res 75:451–460
Konradi C, Heckers S (2003) Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 97:153–179
Li YF, Liu YQ, Huang WC, Luo ZP (2003) Cytoprotective effect is one of common action pathways for antidepressants. Acta Pharmacol Sin 24:996–1000
Li YF, Liu YQ, Yang M, Wang HL, Huang WC, Zhao YM (2004) The cytoprotective effect of inulin-type hexasaccharide extracted from Morinda officinalis on PC12 cells against the lesion induced by corticosterone. Life Sci 75:1531–1538
Li M, Wang Y, Zhang Y, Zhou Z, Yu Z (2008) Elevation of plasma corticosterone levels and hippocampal glucocorticoid receptor translocation in rats: a potential mechanism for cognition impairment following chronic low-power-density microwave exposure. J Radiat Res 49:163–170
Liang B, Moussaif M, Kuan CJ, Gargus JJ, Sze JY (2006) Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metab 4:429–440
Lloyd RB, Nemeroff CB (2011) The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications. Curr Top Med Chem 11:609–617
Lotz GP, Legleiter J, Aron R, Mitchell EJ, Huang SY, Ng C, Glabe C, Thompson LM, Muchowski PJ (2010) Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle. J Biol Chem 285:38183–38193
Menke A, Arloth J, Pütz B, Weber P, Klengel T, Mehta D, Gonik M, Rex-Haffner M, Rubel J, Uhr M, Lucae S, Deussing JM, Müller-Myhsok B, Holsboer F, Binder EB (2012) Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients. Neuropsychopharmacology 37:1455–1464
Morsink MC, Joëls M, Sarabdjitsingh RA, Meijer OC, De Kloet ER, Datson NA (2006) The dynamic pattern of glucocorticoid receptor-mediated transcriptional responses in neuronal PC12 cells. J Neurochem 99:1282–1298
Murphy BE (1991) Steroids and depression. J Steroid Biochem Mol Biol 38:537–559
Murphy BE (1997) Antiglucocorticoid therapies in major depression: a review. Psychoneuroendocrinology 22:S125–S132
Nakano M, Osada K, Misonoo A, Fujiwara K, Takahashi M, Ogawa Y, Haga T, Kanai S, Tanaka D, Sasuga Y, Yanagida T, Asakura M, Yamaguchi N (2010) Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells. Life Sci 86:309–314
Oliveira M, Rodrigues AJ, Leão P, Cardona D, Pêgo JM, Sousa N (2012) The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses. Psychopharmacology (Berl) 220:443–453
Perkinton MS, Sihra TS, Williams RJ (1999) Ca2+-Permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons. J Neurosci 19:5861–5874
Polter A, Yang S, Zmijewska AA, van Groen T, Paik JH, Depinho RA, Peng SL, Jope RS, Li X (2009) Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation. Biol Psychiatry 65:150–159
Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev 53:209–243
Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777
Stetler C, Miller GE (2011) Depression and hypothalamic–pituitary–adrenal activation: a quantitative summary of four decades of research. Psychosom Med 73:114–126
Syed AA, Weaver JU (2005) Glucocorticoid sensitivity: the hypothalamic–pituitary–adrenal–tissue axis. Obes Res 13:1131–1133
Virgin CE Jr, Ha TP, Packan DR, Tombaugh GC, Yang SH, Horner HC, Sapolsky RM (1991) Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity. J Neurochem 57:1422–1428
Voleti B, Duman RS (2012) The roles of neurotrophic factor and Wnt signaling in depression. Clin Pharmacol Ther 91:333–338
Young LT (2002) Neuroprotective effects of antidepressant and mood stabilizing drugs. J Psychiatry Neurosci 27:8–9
Yulug B (2009) Neuroprotective treatment strategies for poststroke mood disorders: a minireview on atypical neuroleptic drugs and selective serotonin re-uptake inhibitors. Brain Res Bull 80:95–99
Zheng WH, Quirion R (2004) Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. J Neurochem 89:844–852
Zheng WH, Quirion R (2009) Glutamate acting on N-methyl-D-aspartate receptors attenuates insulin-like growth factor-1 receptor tyrosine phosphorylation and its survival signaling properties in rat hippocampal neurons. J Biol Chem 284:855–861
Zheng WH, Kar S, Dore S, Quirion R (2000a) Insulin-like growth factor-1 (IGF-1): a neuroprotective trophic factor acting via the Akt kinase pathway. J Neural Transm Suppl 60:261–272
Zheng WH, Kar S, Quirion R (2000b) Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem 275:13377–13385
Zheng WH, Kar S, Quirion R (2002a) FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling. J Neurochem 80:1049–1061
Zheng WH, Kar S, Quirion R (2002b) Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons. Mol Pharmacol 62:225–233
Zheng M, Liu C, Pan F, Shi D, Ma F, Zhang Y, Zhang Y (2011) Protective effects of flavonoid extract from Apocynum venetum leaves against corticosterone-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol 31:421–428
Zhou JZ, Zheng JQ, Zhang YX, Zhou JH (2000) Corticosterone impairs cultured hippocampal neurons and facilitates Ca2+ influx through voltage-dependent Ca2+ channel. Acta Pharmacol Sin 21:156–160
Zhou H, Li X, Gao M (2009) Curcumin protects PC12 cells from corticosterone-induced cytotoxicity: possible involvement of the ERK1/2 pathway. Basic Clin Pharmacol Toxicol 104:236–240
Acknowledgments
This work was supported by the National Natural Science Fund of China (Nos. 30670652, 30711120565, and 30970935), funding from the Chinese State Administration of Foreign Experts Affairs and Administration of Foreign Experts Affairs of Guangdong Province, and funding from the Guangdong Science and Technology Department (Nos. 2009B060700008 and 2011B050200005). We would like to thank Professor Satyabrata Kar (Neurochemical Research Unit, Departments of Medicine and Psychiatry, University of Alberta, Canada) and Micah L. Burch (Department of Medicine, Monash University, Australia) for the language modification.
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Haitao Wang and Xuanhe Zhou contributed equally to this work.
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Wang, H., Zhou, X., Huang, J. et al. The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells. Psychopharmacology 228, 129–141 (2013). https://doi.org/10.1007/s00213-013-3017-9
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DOI: https://doi.org/10.1007/s00213-013-3017-9