Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N-acetylcysteine decreased immobility time (P < 0.05), serum corticosterone (P < 0.001), and hydrogen peroxide (P < 0.001), while restored glutathione concentration. Treatment of the rats with N-acetylcysteine produced significant (P < 0.001) down-regulation of STAT3 mRNA expression and protein phosphorylation. On the other hand, N-acetylcysteine significantly (P < 0.001) increased SOCS3 gene expression; however, SOCS3 protein was not changed. In conclusion, our study suggests that modulation of the JAK/STAT pathway might mediate the antidepressant-like effects of N-acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy.
LopezADMurrayCC. The global burden of disease, 1990-2020. Nat Med1998; 4: 1241–3.
2.
SzaboSTGouldTDManjiHKNeurotransmitters, receptors, signal transduction, and second messengers in psychiatric disorders. In: SchatzbergAFNemeroffCB (eds). Textbook of psychopharmacology, 4th ed. Arlington, VA: American Psychiatric Publishing, 2004, pp. 3–52.
3.
CarrollBJCassidyFNaftolowitzDTathamNEWilsonWHIranmaneshALiuPYVeldhuisJD. Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand2007; 433: 90–103.
4.
LeeBHKimYK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig2010; 7: 231–5.
5.
MössnerRMikovaOKoutsilieriESaoudMEhlisACMüllerNFallgatterAJRiedererP. Consensus paper of the WFSBP task force on biological markers: biological markers in depression. World J Biol Psychiatry2007; 8: 141–74.
6.
MaesMMihaylovaIKuberaMUytterhoevenMVrydagsNBosmansE. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett2009; 30: 470–6.
7.
BehrGAMoreiraJCFreyBN. Preclinical and clinical evidence of antioxidant effects of antidepressant agents: implications for the pathophysiology of major depressive disorder. Oxid Med Cell Longev2012; 2012: 13–13.
8.
MaesMGaleckiPChangYSBerkM. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro) degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry2011; 35: 676–92.
9.
ForlenzaMJMillerGE. Increased serum levels of 8-hydroxy-2’ deoxyguanosine in clinical depression. Psychosom Med2006; 68: 1–7.
10.
DimopoulosNPiperiCPsarraVLeaRWKalofoutisA. Increased plasmalevels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression. Psychiatry Res2008; 161: 59–66.
11.
GaleckiPSzemrajJBienkiewiczMFlorkowskiAGaleckaE. Lipid perox-idation and antioxidant protection in patients during acute depressive episodesand in remission after fluoxetine treatment. Pharmacol Rep2009; 61: 436–47.
12.
YagerSForlenzaMJMillerGE. Depression and oxidative damage to lipids. Psychoneuroendocrinology2010; 35: 1356–62.
13.
NunesSOVReicheEMVMorimotoHKMatsuoTItanoENXavierECYamashitaCMVieiraVRMenoliAVSilvaSSCostaFBReicheFVSilvaFLKaminamiMS. Immune and hormonal activity in adults suffering from depression. Braz J Med Biol Res2002; 35: 581–7.
14.
TakedaKAkiraS. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev2000; 11: 199–207.
15.
JankovicDTrinchieriG. IL-10 or not IL-10: that is the question. Nat Immunol2007; 8: 1281–3.
16.
SoebiyantoRPSreenathSNQuCKLoparoKABuntingKD. Complex systems biology approach to understanding coordination of JAK-STAT signaling. Biosystems2007; 90: 830–42.
17.
NicolasCSAmiciMBortolottoZADohertyACsabaZFafouriADournaudPGressensPCollingridgeGLPeineauS. The role of JAK-STAT signaling within the CNS. JAKSTAT2013; 2: e22925–e22925.
18.
YuCLMeyerDJCampbellGSLarnerACCarter-SuCSchwartzJJoveR. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science1995; 269: 81–3.
19.
HuangS. Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res2007; 13: 1362–6.
20.
SimonRRaiUFanburgBLCochranBH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol1998; 275: 1640–52.
21.
CarballoMCondeMEl BekayRMartín-NietoJCamachoMJMonteseirínJCondeJBedoyaFJSobrinoF. Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes. J Biol Chem1999; 274: 17580–6.
22.
GorinaRSanfeliuCGalitóAMesseguerAPlanasAM. Exposure of glia to pro-oxidant agents revealed selective Stat1 activation by H2O2 and Jak2-independent antioxidant features of the Jak2 inhibitor AG490. Glia2007; 55: 1313–24.
23.
BerkMCopolovDLDeanOLuKJeavonsSSchapkaitzIAnderson-HuntMBushAI. N-acetyl cysteine for depressive symptoms in bipolar disorder – a double-blind randomized placebo-controlled trial. Biol Psychiatry2008; 64: 468–75.
24.
WitschiAReddySStoferBLauterburgBH. The systemic availability of oral glutathione. Eur J Clin Pharmacol1992; 43: 667–9.
25.
HoldinessMR. Clinical pharmokinetics of N-acetylcysteine. Clin Pharmacokinet1991; 20: 123–34.
BerkMCopolovDDeanOLuKJeavonsSSchapkaitzIAnderson-HuntMJuddFKatzFKatzPOrding-JespersenSLittleJConusPCuenodMDoKQBushAI. N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind randomized placebo-controlled trial. Biol Psychiatry2008; 64: 361–8.
28.
FerreiraFRBiojoneCJocaSRGuimarãesFS. Antidepressant-like effects of N-acetyl-L-cysteine in rats. Behav Pharmacol2008; 19: 747–50.
29.
LinckVMCosta-CamposLPilzLKGarciaCRLElisabetskyE. AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test. Behav Pharmacol2012; 23: 171–7.
30.
SmagaIPomiernyBKrzyżanowskaWPomierny-ChamiołoLMiszkielJNiedzielskaEOgórkaAFilipM. N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats. Prog Neuropsychopharmacol Biol Psychiatry2012; 39: 280–7.
31.
FarrSAPoonHFDogrukol-AkDDrakeJBanksWAEyermanEButterfieldDAMorleyJE. The antioxidants alphalipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem2003; 84: 1173–83.
32.
DeanOvan den BuuseMCopolovDBerkMBushA. N-acetylcysteine inhibits depletion of brain glutathione levels in rats: implications for schizophrenia. Int J Neuropsychopharmacol2004; 7: S262–S262.
33.
MoranMMMcFarlandKMelendezRIKalivasPWSeamansJK. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci2005; 25: 6389–93.
34.
Gere-PasztiEJakusJ. The effect of N-acetylcysteine on amphetamine-mediated dopamine release in rat brain striatal slices by ion-pair reversed-phase high performance liquid chromatography. Biomed Chromatogr2009; 23: 658–64.
35.
BelooseskyRWeinerZGinsbergYRossMG. Maternal N-acetyl-cysteine (NAC) protects the rat fetal brain from inflammatory cytokine responses to lipopolysaccharide (LPS). J Matern Fetal Neonatal Med2012; 25: 1324–8.
36.
PorsoltRDLe PichonMJalfreM. Depression: a new animal model sensitive to antidepressant treatment. Nature1977; 266: 730–2.
37.
PorsoltRDAntonGBlavetNJalfreM. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol1978; 47: 379–91.
38.
CryanJFLuckiI. 5-HT4 receptors do not mediate the antidepressant-like behavioral effects of fluoxetine in a modified forced swim test. Eur J Pharmacol2000; 409: 295–9.
39.
GarciaLSComimCMValvassoriSSRéusGZBarbosaAndreazzaACStertzLFriesGRGavioliECKapczinskiFQuevedoJ. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry2008; 32: 140–4.
40.
RiadMZimmerLRbahLWatkinsKCHamonMDescarriesL. Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radiolig and [18F]MPPF in the nucleus raphe dorsalis of rat. J Neurosci2004; 24: 5420–6.
41.
WalshRNCumminsRA. The open-field test: a critical review. Psychol Bull1976; 83: 482–504.
42.
Brenes SáenzJCVillagraORFornaguera TríasJ. Factor analysis of forced swimming test, sucrose preference test and open field test on enriched, social and isolated reared rats. Behav Brain Res2006; 169: 57–65.
43.
KaruriAREngelkingLRKumarMSA. Effects of halothane and methoxyflurane on the hypothalamic-pituitary-adrenal axis in rat. Brain Res Bull1998; 47: 205–9.
44.
ZhouMDiwuZPanchuk-VoloshinaNHauglandRP. A stable nonfluorescent derivative of resorufin for the fluorometric determination of trace hydrogen peroxide: applications in detecting the activity of phagocyte NADPH oxidase and other oxidases. Anal Biochem1997; 253: 162–8.
LivakKJSchmittgenTD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods2001; 25: 402–8.
47.
BradfordMM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem1976; 72: 248–54.
48.
BerkMMalhiGSGrayLJDeanOM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci2013; 34: 167–77.
49.
DeanOGiorlandoFBerkM. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci2011; 36: 78–86.
50.
BorsiniFMeliA. Is the forced swimming test a suitable model for revealing antidepressant activity?Psychopharmacol1988; 94: 147–60.
51.
DinanTG. Glucocorticoids and the genesis of depressive illness. A psychobiologicalmodel. Br J Psychiatry1994; 164: 365–71.
52.
DuncanGEKnappDJCarsonSWBreeseGR. Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone. J Pharmacol Exp Ther1998; 285: 579–89.
53.
ConnorTJKelliherPHarkinAKellyJPLeonardBE. Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat. Euro J Pharmacol1999; 379: 125–33.
54.
KarandreaDKittasCKitrakiE. Forced swimming differential affects male and female brain corticosteroid receptors. Neuroendocrinology2002; 75: 217–26.
55.
TyrkaARMelloAFMelloMFGagneGGGroverKEAndersonGMPriceLHCarpenterLL. Temperament and hypothalamic-pituitary-adrenal axis function in healthy adults. Psychoneuroendocrinology2006; 31: 1036–45.
56.
FavaMKendlerKS. Major depressive disorder. Neuron2000; 28: 335–41.
57.
WalkerFR. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression?Neuropharmacology2013; 67: 304–17.
58.
PageM.EDetkeMJDalviAKirbyLGLuckiI. Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology1999; 147: 162–7.
59.
ArmarioAGarcia-MarquezC. Tricyclic antidepressants activate the pituitary–adrenal axis in the rat. Tolerance to repeated drug administration. Eur J Pharmacol1987; 140: 239–44.
60.
ChenYKongLDXiaXKungHFZhangL. Behavioral and biochemical studies of total furocoumarins from seeds of Psoralea corylifolia in the forced swimming test in mice. J Ethnopharmacol2005; 96: 451–9.
61.
HolsboerFBardenN. Antidepressants and hypothalamic-pituitary- adrenocortical regulation. Endocrin Rev1996; 17: 187–205.
62.
ConnorTJKelliherPShenYHarkinAKellyJPLeonardBE. Effect of subchronic antidepressant treatments on behavioral, neurochemical, and endocrine changes in the forced-swim test. Pharmacol Biochem Behav2000; 65: 591–7.
63.
FeldmanSNewmanMEGurEWeidenfeldJ. Role of serotonin in the amygdale in hypothalamo-pituitaryadrenocortical receptors. Neuroreport1998; 9: 2007–9.
64.
MatésJMSánchez-JiménezF. Antioxidant enzymes and their implications in pathophysiologic processes. Front Biosc1999; 4: 339–45.
65.
SenCKPackerL. Antioxidant and redox regulation of gene transcription. FASEB J1996; 10: 709–20.
66.
LobatoKRCardosoCCBinfaréRWBudniJWagnerCLBrocardoPSde SouzaLFBrocardoCFleschSFreitasAEDafréALRodriguesAL. α-Tocopherol administration produces an antidepressant-like effect in predictive animal models of depression. Behav Brain Res2010; 209: 249–59.
67.
MorettiMBudniJRibeiroCMRodriguesAL. Involvement of different types of potassium channels in the antidepressant-like effect of ascorbic acid in the mouse tail suspension test. Eur J Pharmacol2012; 687: 21–7.
68.
MaesMMihaylovaIKuberaMUytterhoevenMVrydagsNBosmansE. Increased plasma peroxides and serum oxidized low density lipoprotein antibodies in major depression: markers that further explain the higher incidence of neurodegeneration and coronary artery disease. J Affect Disord2010; 125: 287–94.
69.
GawrylukJW1WangJFAndreazzaACShaoLYoungLT. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol2011; 14: 123–30.
70.
GrinbergLFibachEAmerJAtlasD. N-acetylcysteine amide, a novel cell permeating thiol, restores cellular glutathione and protects human red blood cells from oxidative stress. Free Radic Biol Med2005; 38: 136–45.
71.
SadowskaAMManuel-y-KeenoyBDe BackerWA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther2007; 20: 9–22.
72.
ZafirAAraABanuN. In vivo antioxidant status: a putative target of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry2009; 33: 220–8.
73.
GałeckiPSzemrajJBieńkiewiczMZboralskiKGałeckaE. Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol2009; 24: 277–86.
74.
LotrichFEEl-GabalawyHGuentherLCWareCF. The role of inflammation in the pathophysiology of depression: different treatments and their effects. J Rheumatol Suppl2011; 88: 48–54.
75.
LeonardBMaesM. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev2012; 36: 764–85.
76.
ShuaiK1ZiemieckiAWilksAFHarpurAGSadowskiHBGilmanMZDarnellJE. Polypeptide signaling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature1993; 366: 580–3.
77.
GamouSShimizuN. Hydrogen peroxide preferentially enhances the tyrosine phosphorylation of epidermal growth factor receptor. FEBS Lett. 357: 161–4.
78.
VelazquezLFellousMStarkGRPellegriniS. A protein tyrosine kinase in the interferon-a/b signaling pathway. Cell1992; 70: 313–22.
79.
Parker-AthillE1LuoDBaileyAGiuntaBTianJShytleRDMurphyTLegradiGTanJ. Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol2009; 217: 20–7.
80.
RawlingsJSRoslerKMHarrisonDA. The JAK/STAT signaling pathway. J Cell Sci2004; 117: 1281–3.
81.
KojerK1BienMGangelHMorganBDickTPRiemerJ. Glutathione redox potential in the mitochondrial intermembrane space is linked to the cytosol and impacts the Mia40 redox state. EMBO J2012; 31: 3169–82.
82.
XieY1KoleSPrechtPPazinMJBernierM. S-glutathionylation impairs signal transducer and activator oftranscription 3 activation and signaling. Endocrinology2009; 150: 1122–31.
83.
MurrayPJ. The JAK–STAT signaling pathway: input and output integration. J Immunol2007; 178: 2623–9.
84.
FumagalliFMolteniRCalabreseFFrascaARacagniGRivaMA. Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain. J Neurochem2005; 93: 1551–60.
85.
TsaoCWLinYSChengJTLinCFWuHTWuSRTsaiWH. Interferon-alpha-induced serotonin uptake in Jurkat T cells via mitogen-activated protein kinase and transcriptional regulation of the serotonin transporter. J Psychopharmacol2008; 22: 753–60.
86.
EinatH1YuanPGouldTDLiJDuJZhangLManjiHKChenG. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci2003; 23: 7311–16.
87.
LiXZhuWRohMSFriedmanABRosboroughKJopeRS. In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain. Neuropsychopharmacology2004; 29: 1426–31.
88.
MingmalairakSTohdaMMurakamiYMatsumotoK. Possible involvement of signal transducers and activators of transcription 3 system on depression in the model mice brain. Biol Pharm Bull2010; 33: 636–40.
89.
O’SullivanLALiongueCLewisRSStephensonSEWardAC. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol2007; 44: 2497–506.
