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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes

Authors: Simona Daniele, Elisa Zappelli, Claudia Martini

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

In the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up-regulating inflammatory processes. Reactive astrocytes and microglia are associated with the pathophysiology of neuronal injury, neurodegenerative diseases and major depression, in both animal models and human brains. Several studies have reported clear anti-inflammatory effects of anti-depressant treatment on astrocytes, especially in models of neurological disorders. Trazodone (TDZ) is a triazolopyridine derivative that is structurally unrelated to other major classes of antidepressants. Although the molecular mechanisms of TDZ in neurons have been investigated, it is unclear whether astrocytes are also a TDZ target.

Methods

The effects of TDZ on human astrocytes were investigated in physiological conditions and following inflammatory insult with lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α). Astrocytes were assessed for their responses to pro-inflammatory mediators and cytokines, and the receptors and signalling pathways involved in TDZ-mediated effects were evaluated.

Results

TDZ had no effect on cell proliferation, but it decreased pro-inflammatory mediator release and modulated trophic and transcription factor mRNA expression. Following TDZ treatment, the AKT pathway was activated, whereas extracellular signal-regulated kinase and c-Jun NH2-terminal kinase were inhibited. Most importantly, a 72-h TDZ pre-treatment before inflammatory insult completely reversed the anti-proliferative effects induced by LPS-TNF-α. The expression or the activity of inflammatory mediators, including interleukin-6, c-Jun NH2-terminal kinase and nuclear factor κB, were also reduced. Furthermore, TDZ affected astrocyte metabolic support to neurons by counteracting the inflammation-mediated lactate decrease. Finally, TDZ protected neuronal-like cells against neurotoxicity mediated by activated astrocytes. These effects mainly involved an activation of 5-HT1A and an antagonism at 5-HT2A/C serotonin receptors. Fluoxetine, used in parallel, showed similar final effects nevertheless it activates different receptors/intracellular pathways.

Conclusions

Altogether, our results demonstrated that TDZ directly acts on astrocytes by regulating intracellular signalling pathways and increasing specific astrocyte-derived neurotrophic factor expression and lactate release. TDZ may contribute to neuronal support by normalizing trophic and metabolic support during neuroinflammation, which is associated with neurological diseases, including major depression.
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Literature
1.
Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease—a double-edged sword. Neuron. 2002;35:419–32.CrossRefPubMed
2.
3.
Aloisi F. The role of microglia and astrocytes in CNS immune surveillance and immunopathology. Adv Exp Med Biol. 1999;468:123–33.CrossRefPubMed
4.
De Keyser J, Mostert JP, Koch MW. Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci. 2008;267:3–16.CrossRefPubMed
5.
Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417:39–44.CrossRefPubMed
6.
Horner PJ, Palmer TD. New roles for astrocytes: the nightlife of an 'astrocyte'. La vida loca! Trends Neurosci. 2003;26:597–603.CrossRefPubMed
7.
Fernandes A, Silva RF, Falcão AS, Brito MA, Brites D. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS. J Neuroimmunol. 2004;153:64–75.CrossRefPubMed
8.
9.
Hopkins SJ, Rothwell NJ. Cytokines and the nervous system. I: expression and recognition. Trends Neurosci. 1995;18:83–8.CrossRefPubMed
10.
Gayle DA, Ling Z, Tong C, Landers T, Lipton JW, Carvey PM. Lipopolysaccharide (LPS)-induced dopamine cell loss in culture: roles of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide. Brain Res Dev Brain Res. 2002;133:27–35.CrossRefPubMed
11.
Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, et al. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem. 2004;279:1415–21.CrossRefPubMed
12.
Zeinstra E, Wilczak N, De Keyser J. Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2. J Neuroimmunol. 2003;135:166–71.CrossRefPubMed
13.
Depino AM, Earl C, Kaczmarczyk E, Ferrari C, Besedovsky H, del Rey A, et al. Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease. Eur J Neurosci. 2003;18:2731–42.CrossRefPubMed
14.
Avila-Muñoz E, Arias C. When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer's disease. Ageing Res Rev. 2014;18:29–40.CrossRefPubMed
15.
Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.PubMedCentralPubMed
16.
Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex. 2002;12:386–94.CrossRefPubMed
17.
Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45:1085–98.CrossRefPubMed
18.
Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A. 2005;102:15653–8.PubMedCentralCrossRefPubMed
19.
Si X, Miguel-Hidalgo JJ, O'Dwyer G, Stockmeier CA, Rajkowska G. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology. 2004;29:2088–96.PubMedCentralCrossRefPubMed
20.
21.
Hwang J, Zheng LT, Ock J, Lee MG, Kim SH, Lee HW, et al. Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants. Neuropharmacology. 2008;55:826–34.CrossRefPubMed
22.
Vollmar P, Haghikia A, Dermietzel R, Faustmann PM. Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model. Int J Neuropsychopharmacol. 2008;11:111–7.CrossRefPubMed
23.
Zhu J, Wei X, Liu J, Hu Y, Xu J. Interaction of glia activation and neurotransmission in hippocampus of neuropathic rats treated with mirtazapine. Exp Clin Psychopharmacol. 2009;17:198–203.CrossRefPubMed
24.
Czéh B, Simon M, Schmelting B, Hiemke C, Fuchs E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2006;31:1616–26.CrossRefPubMed
25.
Allaman I, Fiumelli H, Magistretti PJ, Martin JL. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology (Berl). 2011;216:75–84.CrossRef
26.
Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008;322:1551–5.CrossRefPubMed
27.
Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14:536–46.PubMed
28.
Odagaki Y, Toyoshima R, Yamauchi T. Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPgammaS binding. J Psychopharmacol. 2005;19:235–41.CrossRefPubMed
29.
Daniele S, Da Pozzo E, Zappelli E, Martini C. Trazodone treatment protects neuronal-like cells from inflammatory insult through inhibition of NF-kB, p38 and JNK. Cell Signal. 2015;27:1609–29.CrossRefPubMed
30.
Marinescu IP, Predescu A, Udriştoiu T, Marinescu D. Comparative study of neuroprotective effect of tricyclics vs. trazodone on animal model of depressive disorder. Rom J Morphol Embryol. 2012;53:397–400.PubMed
31.
Gaur V, Kumar A. Protective effect of desipramine, venlafaxine and trazodone against experimental animal model of transient global ischemia: possible involvement of NO-cGMP pathway. Brain Res. 2010;1353:204–12.CrossRefPubMed
32.
Sébire G, Emilie D, Wallon C, Héry C, Devergne O, Delfraissy JF, et al. In vitro production of IL-6, IL-1 beta, and tumor necrosis factor-alpha by human embryonic microglial and neural cells. J Immunol. 1993;150:1517–23.PubMed
33.
Laureys G, Gerlo S, Spooren A, Demol F, De Keyser J, Aerts JL. β-adrenergic agonists modulate TNF-α induced astrocytic inflammatory gene expression and brain inflammatory cell populations. J Neuroinflammation. 2014;11:21.PubMedCentralCrossRefPubMed
34.
Abd-El-Basset EM. Pro-inflammatory cytokine; tumor-necrosis factor-alpha (TNF-α) inhibits astrocytic support of neuronal survival and neurites outgrowth. Advances in Bioscience and Biotechnology. 2013;4:73–80.CrossRef
35.
Kalmár B, Kittel A, Lemmens R, Környei Z, Madarász E. Cultured astrocytes react to LPS with increased cyclooxygenase activity and phagocytosis. Neurochem Int. 2001;38:453–61.CrossRefPubMed
36.
Juric DM, Loncar D, Carman-Krzan M. Noradrenergic stimulation of BDNF synthesis in astrocytes: mediation via alpha1- and beta1/beta2-adrenergic receptors. Neurochem Int. 2008;52:297–306.CrossRefPubMed
37.
Cliffe IA, Brightwell CI, Fletcher A, Forster EA, Mansell HL, Reilly Y, et al. (S)-N-tert-butyl-3-(4-(2-methoxyphenyl) -piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors. J Med Chem. 1993;36:1509–10.CrossRefPubMed
38.
Skingle M, Sleight AJ, Feniuk W. Effects of the 5-HT1D receptor antagonist GR127935 on extracellular levels of 5-HT in the guinea-pig frontal cortex as measured by microdialysis. Neuropharmacology. 1995;34:377–82.CrossRefPubMed
39.
Bonhaus DW, Flippin LA, Greenhouse RJ, Jaime S, Rocha C, Dawson M, et al. RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist. Br J Pharmacol. 1999;127:1075–82.PubMedCentralCrossRefPubMed
40.
Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, et al. Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004;370:114–23.CrossRefPubMed
41.
Bétry C, Pehrson AL, Etiévant A, Ebert B, Sánchez C, Haddjeri N. The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT(3) receptor antagonism. Int J Neuropsychopharmacol. 2013;16:1115–27.CrossRefPubMed
42.
Crews CM, Alessandrini A, Erikson RL. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science. 1992;258:478–80.CrossRefPubMed
43.
Giacomelli C, Trincavelli ML, Satriano C, Hansson Ö, La Mendola D, Rizzarelli E, et al. Copper (II) ions modulate Angiogenin activity in human endothelial cells. Int J Biochem Cell Biol. 2015;60:185–96.
44.
Daniele S, Trincavelli ML, Fumagalli M, Zappelli E, Lecca D, Bonfanti E, et al. Does GRK-β arrestin machinery work as a "switch on" for GPR17-mediated activation of intracellular signaling pathways? Cell Signal. 2014;26:1310–25.CrossRefPubMed
45.
van Neerven S, Nemes A, Imholz P, Regen T, Denecke B, Johann S, et al. Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid. J Neuroimmunol. 2010;229:169–79.CrossRefPubMed
46.
47.
Lisi L, Navarra P, Feinstein DL, Dello RC. The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes. J Neuroinflammation. 2011;8:1.PubMedCentralCrossRefPubMed
48.
Buzas B, Rosenberger J, Kim KW, Cox BM. Inflammatory mediators increase the expression of nociceptin/orphanin FQ in rat astrocytes in culture. Glia. 2002;39:237–46.CrossRefPubMed
49.
Yabe T, Sanagi T, Schwartz JP, Yamada H. Pigment epithelium-derived factor induces pro-inflammatory genes in neonatal astrocytes through activation of NF-kappa B and CREB. Glia. 2005;50:223–34.CrossRefPubMed
50.
Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1:1–14.CrossRef
51.
Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioural responses. Biol Psychiatry. 2013;74:742–9.CrossRefPubMed
52.
Zschocke J, Zimmermann N, Berning B, Ganal V, Holsboer F, Rein T. Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons—dissociation from cholesterol homeostasis. Neuropsychopharmacology. 2011;36:1754–68.PubMedCentralCrossRefPubMed
53.
54.
Li CY, Li X, Liu SF, Qu WS, Wang W, Tian DS. Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation. Neurochem Int. 2015;83–84:9–18.CrossRefPubMed
55.
Gassen NC, Hartmann J, Zschocke J, Stepan J, Hafner K, Zellner A, et al. Association of FKBP51 with priming of autophagy pathways and mediation of antidepressant treatment response: evidence in cells, mice, and humans. PLoS Med. 2014;11:1–20.CrossRef
56.
Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia. 2007;55:1251–562.CrossRefPubMed
57.
Myer DJ, Gurkoff GG, Lee SM, Hovda DA, Sofroniew MV. Essential protective roles of reactive astrocytes in traumatic brain injury. Brain. 2006;129:2761–72.CrossRefPubMed
58.
Kong EK, Peng L, Chen Y, Yu AC, Hertz L. Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration. Neurochem Res. 2002;27:113–20.CrossRefPubMed
59.
Wong DT, Bymaster FP. Development of antidepressant drugs. Fluoxetine (Prozac) and other selective serotonin uptake inhibitors. Adv Exp Med Biol. 1995;363:77–95.CrossRefPubMed
60.
Peng L, Gu L, Li B, Hertz L. Fluoxetine and all other SSRIs are 5-HT2B agonists—importance for their therapeutic effects. Curr Neuropharmacol. 2014;12:365–79.PubMedCentralCrossRefPubMed
61.
Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramaugé M, Courtin F, et al. MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. J Mol Neurosci. 2004;24:207–16.CrossRefPubMed
62.
Di Benedetto B, Kühn R, Nothdurfter C, Rein T, Wurst W. Rupprecht R.N-desalkylquetiapine activates ERK1/2 to induce GDNF release in C6 glioma cells: a putative cellular mechanism for quetiapine as antidepressant. Neuropharmacology. 2012;62:209–16.CrossRefPubMed
63.
Hisaoka K, Tsuchioka M, Yano R, Maeda N, Kajitani N, Morioka N, et al. Tricyclic antidepressant amitriptyline activates fibroblast growth factor receptor signaling in glial cells: involvement in glial cell line-derived neurotrophic factor production. J Biol Chem. 2011;286:21118–28.PubMedCentralCrossRefPubMed
64.
Li B, Zhang S, Li M, Hertz L, Peng L. Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation. Psychopharmacology (Berl). 2009;207:1–12.CrossRef
65.
Li B, Zhang S, Zhang H, Nu W, Cai L, Hertz L, et al. Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation. Psychopharmacology (Berl). 2008;201:443–58.CrossRef
66.
Pang T, Wang J, Benicky J, Sánchez-Lemus E, Saavedra JM. Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation. 2012;9:102.PubMedCentralCrossRefPubMed
67.
Li YH, Zhang CH, Qiu J, Wang SE, Hu SY, Huang X, et al. Antidepressant-like effects of Chaihu-Shugan-San via SAPK/JNK signal transduction in rat models of depression. Pharmacogn Mag. 2014;10:271–7.PubMedCentralCrossRefPubMed
68.
69.
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–62.PubMedCentralCrossRefPubMed
70.
Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012;7:42–59.CrossRefPubMed
71.
Bracchi-Ricard V, Lambertsen KL, Ricard J, Nathanson L, Karmally S, Johnstone J, et al. Inhibition of astroglial NF-κB enhances oligodendrogenesis following spinal cord injury. J Neuroinflammation. 2013;10:92.PubMedCentralCrossRefPubMed
72.
Gramsbergen JB, Cumming P. Serotonin mediates rapid changes of striatal glucose and lactate metabolism after systemic 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") administration in awake rats. Neurochem Int. 2007;51:8–15.CrossRefPubMed
73.
Gavillet M, Allaman I, Magistretti PJ. Modulation of astrocytic metabolic phenotype by proinflammatory cytokines. Glia. 2008;56:975–89.CrossRefPubMed
74.
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830–43.CrossRefPubMed
75.
Liu RP, Zou M, Wang JY, Zhu JJ, Lai JM, Zhou LL, et al. Paroxetine ameliorates lipopolysaccharide-induced microglia activation via differential regulation of MAPK signaling. J Neuroinflammation. 2014;11:47.PubMedCentralCrossRefPubMed
76.
Launay JM, Schneider B, Loric S, Da Prada M, Kellermann O. Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB J. 2006;20:1843–54.CrossRefPubMed
77.
Diaz SL, Doly S, Narboux-Nême N, Fernández S, Mazot P, Banas SM, et al. 5-HT(2B) receptors are required for serotonin-selective antidepressant actions. Mol Psychiatry. 2012;17:154–63.PubMedCentralCrossRefPubMed
78.
Hertz L, Li B, Song D, Ren J, Dong L, Chen Y, et al. Astrocytes as a 5-HT2B-mediated SERT-independent SSRI target, slowly altering depression-associated genes and function. Current Signal Transduction Therapy. 2012;7:65–80.CrossRef
79.
Birnbaumer L. Expansion of signal transduction by G proteins. The second 15 years or so: from 3 to 16 alpha subunits plus betagamma dimers. Biochim Biophys Acta. 2007;1768:772–93.PubMedCentralCrossRefPubMed
80.
81.
Crane JW, Shimizu K, Carrasco GA, Garcia F, Jia C, Sullivan NR, et al. 5-HT1A receptors mediate (+)8-OH-DPAT-stimulation of extracellular signal-regulated kinase (MAP kinase) in vivo in rat hypothalamus: time dependence and regional differences. Brain Res. 2007;1183:51–9.
82.
Buritova J, Berrichon G, Cathala C, Colpaert F, Cussac D. Region-specific changes in 5-HT1A agonist-induced extracellular signal-regulated kinases 1/2 phosphorylation in rat brain: a quantitative ELISA study. Neuropharmacology. 2009;56:350–61.CrossRefPubMed
83.
Chen J, Shen C, Meller E. 5-HT1A receptor-mediated regulation of mitogen-activated protein kinase phosphorylation in rat brain. Eur J Pharmacol. 2002;452:155–62.CrossRefPubMed
84.
Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry. 2006;11:1116–25.CrossRefPubMed
85.
Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry. 2009;14:51–9.CrossRefPubMed
86.
Hunsberger J, Austin DR, Henter ID, Chen G. The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci. 2009;11:333–48.PubMedCentralPubMed
87.
Kong PJ, Byun JS, Lim SY, Lee JJ, Hong SJ, Kwon KJ, et al. Melatonin induces Akt phosphorylation through melatonin receptor- and PI3K-dependent pathways in primary astrocytes. Korean J Physiol Pharmacol. 2008;12:37–41.PubMedCentralCrossRefPubMed
88.
Li B, Du T, Li H, Gu L, Zhang H, Huang J, et al. Signalling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons. Br J Pharmacol. 2008;154:191–203.PubMedCentralCrossRefPubMed
89.
Hsiung SC, Tamir H, Franke TF, Liu KP. Roles of extracellular signal-regulated kinase and Akt signaling in coordinating nuclear transcription factor-kappaB-dependent cell survival after serotonin 1A receptor activation. J Neurochem. 2005;95:1653–66.CrossRefPubMed
90.
Hsiung SC, Tin A, Tamir H, Franke TF, Liu KP. Inhibition of 5-HT1A receptor-dependent cell survival by cAMP/protein kinase A: role of protein phosphatase 2A and Bax. J Neurosci Res. 2008;86:2326–38.CrossRefPubMed
91.
Gould TD, Picchini AM, Einat H, Manji HK. Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Curr Drug Targets. 2006;7:1399–409.CrossRefPubMed
92.
Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, et al. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A. 2008;105:1333–8.PubMedCentralCrossRefPubMed
93.
Beaulieu JM, Del'guidice T, Sotnikova TD, Lemasson M, Gainetdinov RR. Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors. Front Mol Neurosci. 2011;4:38.PubMedCentralCrossRefPubMed
94.
Jung HW, Chung YS, Kim YS, Park YK. Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells. Exp Mol Med. 2007;39:715–21.CrossRefPubMed
Metadata
Title
Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes
Authors
Simona Daniele
Elisa Zappelli
Claudia Martini
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0446-x

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