The antidepressant-like effect of guanosine is dependent on GSK-3β inhibition and activation of MAPK/ERK and Nrf2/heme oxygenase-1 signaling pathways

  • Priscila B. Rosa
  • Luis E. B. Bettio
  • Vivian B. Neis
  • Morgana Moretti
  • Isabel Werle
  • Rodrigo B. Leal
  • Ana Lúcia S. RodriguesEmail author
Original Article


Although guanosine is an endogenous nucleoside that displays antidepressant-like properties in several animal models, the mechanism underlying its antidepressant-like effects is not well characterized. The present study aimed at investigating the involvement of ERK/GSK-3β and Nrf2/HO-1 signaling pathways in the antidepressant-like effect of guanosine in the mouse tail suspension test (TST). The immobility time in the TST was taken as an indicative of antidepressant-like responses and the locomotor activity was assessed in the open-field test. Biochemical analyses were performed by Western blotting in the hippocampus and prefrontal cortex (PFC). The combined treatment with sub-effective doses of guanosine (0.01 mg/kg, p.o.) and lithium chloride (a non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01 μg/site, i.c.v.) produced a synergistic antidepressant-like effect in the TST. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) was completely prevented by the treatment with MEK1/2 inhibitors U0126 (5 μg/site, i.c.v.), PD98059 (5 μg/site, i.c.v.), or zinc protoporphyrin IX (ZnPP) (HO-1 inhibitor, 10 μg/site, i.c.v). Guanosine administration (0.05 mg/kg, p.o.) increased the immunocontent of β-catenin in the nuclear fraction and Nrf2 in the cytosolic fraction in the hippocampus and PFC. The immunocontent of HO-1 was also increased in the hippocampus and PFC. Altogether, the results provide evidence that the antidepressant-like effect of guanosine in the TST involves the inhibition of GSK-3β, as well as activation of MAPK/ERK and Nrf2/HO-1 signaling pathways, highlighting the relevance of these molecular targets for antidepressant responses.


Antidepressant ERK GSK-3β Guanosine HO-1 Nrf2 



ALSR and RBL are recipients of CNPq Research Productivity Fellowship. The authors would like to thank the Multiuser Laboratory for Biological Studies (LAMEB), UFSC, for the support.

Funding information

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) #449436/2014-4, #310113/2017-2, and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES).

Compliance with ethical standards

All experiments were performed in accordance with the Guidelines of Ethic Committee on Animal Use of the Federal University of Santa Catarina (CEUA/UFSC) the guidelines laid down by the NIH (NIH Guide for the Care and Use of Laboratory Animals) in the USA. The CEUA/UFSC has approved all experimental protocols (approval numbers 00795 and 7485180518).

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59(12):1151–1159. CrossRefPubMedGoogle Scholar
  2. 2.
    Nemeroff CB (2007) The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res 41(3–4):189–206. CrossRefPubMedGoogle Scholar
  3. 3.
    Global Burden of Disease Study C (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386(9995):743–800. CrossRefGoogle Scholar
  4. 4.
    Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7(2):137–151. CrossRefPubMedGoogle Scholar
  5. 5.
    Agius M, Bonnici H (2017) Antidepressants in use in clinical practice. Psychiatr Danub 29(Suppl 3):667–671PubMedGoogle Scholar
  6. 6.
    Dwyer JM, Duman RS (2013) Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry 73(12):1189–1198. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lee JS, Surh YJ (2005) Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 224(2):171–184. CrossRefPubMedGoogle Scholar
  8. 8.
    Uruno A, Motohashi H (2011) The Keap1-Nrf2 system as an in vivo sensor for electrophiles. Nitric Oxide 25(2):153–160. CrossRefPubMedGoogle Scholar
  9. 9.
    Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244(1):37–42. CrossRefPubMedGoogle Scholar
  10. 10.
    Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 99(18):11908–11913. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Neis VB, Rosa PB, Moretti M, Rodrigues ALS (2018) Involvement of heme oxygenase-1 in neuropsychiatric and neurodegenerative diseases. Curr Pharm Des 24(20):2283–2302. CrossRefPubMedGoogle Scholar
  12. 12.
    Martin-de-Saavedra MD, Budni J, Cunha MP, Gomez-Rangel V, Lorrio S, Del Barrio L, Lastres-Becker I, Parada E, Tordera RM, Rodrigues ALS, Cuadrado A, Lopez MG (2013) Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. Psychoneuroendocrinology 38(10):2010–2022. CrossRefPubMedGoogle Scholar
  13. 13.
    Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912. CrossRefPubMedGoogle Scholar
  14. 14.
    Meng XB, Sun GB, Wang M, Sun J, Qin M, Sun XB (2013) P90RSK and Nrf2 activation via MEK1/2-ERK1/2 pathways mediated by notoginsenoside R2 to prevent 6-hydroxydopamine-induced apoptotic death in SH-SY5Y cells. Evid Based Complement Alternat Med 2013:971712. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zou W, Chen C, Zhong Y, An J, Zhang X, Yu Y, Yu Z, Fu J (2013) PI3K/Akt pathway mediates Nrf2/ARE activation in human L02 hepatocytes exposed to low-concentration HBCDs. Environ Sci Technol 47(21):12434–12440. CrossRefPubMedGoogle Scholar
  16. 16.
    Jope RS, Roh MS (2006) Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 7(11):1421–1434. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jope RS (1999) Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry 4(2):117–128CrossRefGoogle Scholar
  18. 18.
    Chen G, Huang LD, Jiang YM, Manji HK (1999) The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 72(3):1327–1330. CrossRefPubMedGoogle Scholar
  19. 19.
    Li X, Bijur GN, Jope RS (2002) Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord 4(2):137–144. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Costemale-Lacoste JF, Guilloux JP, Gaillard R (2016) The role of GSK-3 in treatment-resistant depression and links with the pharmacological effects of lithium and ketamine: a review of the literature. Encephale 42(2):156–164. CrossRefPubMedGoogle Scholar
  21. 21.
    Beurel E, Song L, Jope RS (2011) Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16(11):1068–1070. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li X, Jope RS (2010) Is glycogen synthase kinase-3 a central modulator in mood regulation? Neuropsychopharmacology 35(11):2143–2154. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Garza JC, Guo M, Zhang W, Lu XY (2012) Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3beta/beta-catenin signaling. Mol Psychiatry 17(8):790–808. CrossRefPubMedGoogle Scholar
  24. 24.
    Madsen TM, Newton SS, Eaton ME, Russell DS, Duman RS (2003) Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis. Biol Psychiatry 54(10):1006–1014. CrossRefPubMedGoogle Scholar
  25. 25.
    Ciccarelli R, Ballerini P, Sabatino G, Rathbone MP, D'Onofrio M, Caciagli F, Di Iorio P (2001) Involvement of astrocytes in purine-mediated reparative processes in the brain. Int J Dev Neurosci 19(4):395–414. CrossRefPubMedGoogle Scholar
  26. 26.
    Bettio LE, Gil-Mohapel J, Rodrigues ALS (2016) Guanosine and its role in neuropathologies. Purinergic Signal 12(3):411–426. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Bettio LE, Cunha MP, Budni J, Pazini FL, Oliveira A, Colla AR, Rodrigues ALS (2012) Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways. Behav Brain Res 234(2):137–148. CrossRefPubMedGoogle Scholar
  28. 28.
    Bettio LE, Freitas AE, Neis VB, Santos DB, Ribeiro CM, Rosa PB, Farina M, Rodrigues ALS (2014) Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress. Pharmacol Biochem Behav 127:7–14. CrossRefPubMedGoogle Scholar
  29. 29.
    Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues ALS (2012) Depressive-like behavior induced by tumor necrosis factor-alpha in mice. Neuropharmacology 62(1):419–426. CrossRefPubMedGoogle Scholar
  30. 30.
    Barauna SC, Kaster MP, Heckert BT, do Nascimento KS, Rossi FM, Teixeira EH, Cavada BS, Rodrigues ALS, Leal RB (2006) Antidepressant-like effect of lectin from Canavalia brasiliensis (ConBr) administered centrally in mice. Pharmacol Biochem Behav 85(1):160–169. CrossRefPubMedGoogle Scholar
  31. 31.
    Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85(3):367–370. CrossRefPubMedGoogle Scholar
  32. 32.
    Nascimento-Castro CP, Wink AC, da Fonseca VS, Bianco CD, Winkelmann-Duarte EC, Farina M, Rodrigues ALS, Gil-Mohapel J, de Bem AF, Brocardo PS (2018) Antidepressant effects of probucol on early-symptomatic YAC128 transgenic mice for Huntington’s disease. Neural Plast 2018:4056383. CrossRefGoogle Scholar
  33. 33.
    Neis VB, Manosso LM, Moretti M, Freitas AE, Daufenbach J, Rodrigues ALS (2014) Depressive-like behavior induced by tumor necrosis factor-alpha is abolished by agmatine administration. Behav Brain Res 261:336–344. CrossRefPubMedGoogle Scholar
  34. 34.
    Cunha MP, Budni J, Ludka FK, Pazini FL, Rosa JM, Oliveira A, Lopes MW, Tasca CI, Leal RB, Rodrigues ALS (2016) Involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. Mol Neurobiol 53(5):2954–2968. CrossRefPubMedGoogle Scholar
  35. 35.
    Cunha MP, Budni J, Pazini FL, Oliveira A, Rosa JM, Lopes MW, Leal RB, Rodrigues ALS (2014) Involvement of PKA, PKC, CAMK-II and MEK1/2 in the acute antidepressant-like effect of creatine in mice. Pharmacol Rep 66(4):653–659. CrossRefPubMedGoogle Scholar
  36. 36.
    Manosso LM, Moretti M, Rosa JM, Cunha MP, Rodrigues ALS (2017) Evidence for the involvement of heme oxygenase-1 in the antidepressant-like effect of zinc. Pharmacol Rep 69(3):497–503. CrossRefPubMedGoogle Scholar
  37. 37.
    Ramos-Hryb AB, Cunha MP, Pazini FL, Lieberknecht V, Prediger RDS, Kaster MP, Rodrigues ALS (2017) Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2. Pharmacol Rep 69(6):1240–1246. CrossRefPubMedGoogle Scholar
  38. 38.
    Moretti M, Budni J, Freitas AE, Rosa PB, Rodrigues ALS (2014) Antidepressant-like effect of ascorbic acid is associated with the modulation of mammalian target of rapamycin pathway. J Psychiatr Res 48(1):16–24. CrossRefPubMedGoogle Scholar
  39. 39.
    Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83(2):346–356. CrossRefPubMedGoogle Scholar
  40. 40.
    Cordova FM, Aguiar AS Jr, Peres TV, Lopes MW, Goncalves FM, Remor AP, Lopes SC, Pilati C, Latini AS, Prediger RD, Erikson KM, Aschner M, Leal RB (2012) In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLoS One 7(3):e33057. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF (2016) Major depressive disorder. Nat Rev Dis Primers 2:16065. CrossRefPubMedGoogle Scholar
  42. 42.
    Schmidt AP, Bohmer AE, Schallenberger C, Antunes C, Tavares RG, Wofchuk ST, Elisabetsky E, Souza DO (2010) Mechanisms involved in the antinociception induced by systemic administration of guanosine in mice. Br J Pharmacol 159(6):1247–1263. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Vinade ER, Schmidt AP, Frizzo ME, Portela LV, Soares FA, Schwalm FD, Elisabetsky E, Izquierdo I, Souza DO (2005) Effects of chronic administered guanosine on behavioral parameters and brain glutamate uptake in rats. J Neurosci Res 79(1–2):248–253. CrossRefPubMedGoogle Scholar
  44. 44.
    Neis VB, Moretti M, Bettio LE, Ribeiro CM, Rosa PB, Gonçalves FM, Lopes MW, Leal RB, Rodrigues ALS (2016) Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling. Eur Neuropsychopharmacol 26(6):959–971. CrossRefGoogle Scholar
  45. 45.
    Ludka FK, Constantino LC, Dal-Cim T, Binder LB, Zomkowski A, Rodrigues ALS, Tasca CI (2016) Involvement of PI3K/Akt/GSK-3beta and mTOR in the antidepressant-like effect of atorvastatin in mice. J Psychiatr Res 82:50–57. CrossRefPubMedGoogle Scholar
  46. 46.
    Rosa JM, Pazini FL, Cunha MP, Colla ARS, Manosso LM, Mancini G, Souza ACG, de Bem AF, Prediger RD, Rodrigues ALS (2018) Antidepressant effects of creatine on amyloid beta1-40-treated mice: the role of GSK-3beta/Nrf2 pathway. Prog Neuro-Psychopharmacol Biol Psychiatry 86:270–278. CrossRefGoogle Scholar
  47. 47.
    Rosa AO, Kaster MP, Binfare RW, Morales S, Martin-Aparicio E, Navarro-Rico ML, Martinez A, Medina M, Garcia AG, Lopez MG, Rodrigues ALS (2008) Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 32(6):1549–1556. CrossRefGoogle Scholar
  48. 48.
    Silva R, Mesquita AR, Bessa J, Sousa JC, Sotiropoulos I, Leão P, Almeida OF, Sousa N (2008) Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3beta. Neuroscience 152(3):656–669. CrossRefGoogle Scholar
  49. 49.
    Oh DH, Park YC, Kim SH (2010) Increased glycogen synthase kinase-3beta mRNA level in the hippocampus of patients with major depression: a study using the Stanley neuropathology consortium integrative database. Psychiatry Investig 7(3):202–207. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4(2):68–75. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338(6103):68–72. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Coyle JT, Duman RS (2003) Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38(2):157–160. CrossRefPubMedGoogle Scholar
  53. 53.
    Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H (2004) Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry 55(8):781–784. CrossRefPubMedGoogle Scholar
  54. 54.
    Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 92(17):7686–7689. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273(29):18623–18632. CrossRefPubMedGoogle Scholar
  56. 56.
    Manosso LM, Moretti M, Ribeiro CM, Gonçalves FM, Leal RB, Rodrigues ALS (2015) Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuro-Psychopharmacol Biol Psychiatry 59:59–67. CrossRefGoogle Scholar
  57. 57.
    Surh YJ, Kundu JK, Li MH, Na HK, Cha YN (2009) Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress. Arch Pharm Res 32(8):1163–1176. CrossRefPubMedGoogle Scholar
  58. 58.
    Qin S, Hou DX (2016) Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals. Mol Nutr Food Res 60(8):1731–1755. CrossRefPubMedGoogle Scholar
  59. 59.
    Li B, Jeong GS, Kang DG, Lee HS, Kim YC (2009) Cytoprotective effects of lindenenyl acetate isolated from Lindera strychnifolia on mouse hippocampal HT22 cells. Eur J Pharmacol 614(1–3):58–65. CrossRefPubMedGoogle Scholar
  60. 60.
    Zhao X, Wang R, Xiong J, Yan D, Li A, Wang S, Xu J, Zhou J (2017) JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2. Toxicol Lett 277:32–40. CrossRefPubMedGoogle Scholar
  61. 61.
    Nguyen T, Sherratt PJ, Huang HC, Yang CS, Pickett CB (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem 278(7):4536–4541. CrossRefPubMedGoogle Scholar
  62. 62.
    Stewart D, Killeen E, Naquin R, Alam S, Alam J (2003) Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem 278(4):2396–2402. CrossRefPubMedGoogle Scholar
  63. 63.
    Tan Y, Wang Q, She Y, Bi X, Zhao B (2015) Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF-kappaB suppression. J Trauma Acute Care Surg 78(4):784–792. CrossRefPubMedGoogle Scholar
  64. 64.
    Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284(20):13291–13295. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Karapetian RN, Evstafieva AG, Abaeva IS, Chichkova NV, Filonov GS, Rubtsov YP, Sukhacheva EA, Melnikov SV, Schneider U, Wanker EE, Vartapetian AB (2005) Nuclear oncoprotein prothymosin alpha is a partner of Keap1: implications for expression of oxidative stress-protecting genes. Mol Cell Biol 25(3):1089–1099. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Velichkova M, Hasson T (2005) Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol Cell Biol 25(11):4501–4513. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Hsu M, Muchova L, Morioka I, Wong RJ, Schroder H, Stevenson DK (2006) Tissue-specific effects of statins on the expression of heme oxygenase-1 in vivo. Biochem Biophys Res Commun 343(3):738–744. CrossRefPubMedGoogle Scholar
  68. 68.
    Quincozes-Santos A, Bobermin LD, Souza DG, Bellaver B, Gonçalves CA, Souza DO (2014) Guanosine protects C6 astroglial cells against azide-induced oxidative damage: a putative role of heme oxygenase 1. J Neurochem 130(1):61–74. CrossRefGoogle Scholar
  69. 69.
    Bellaver B, Souza DG, Bobermin LD, Gonçalves CA, Souza DO, Quincozes-Santos A (2015) Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway. Purinergic Signal 11(4):571–580. CrossRefGoogle Scholar
  70. 70.
    De Bem A, Engel D, de Oliveira J, Moreira EL, Neis VB, Santos DB, Lopes JB, Rodrigues ALS, Brocardo P (2014) Hypercholesterolemia as a risk factor for depressive disorder? Free Radic Biol Med 75 Suppl 1:S28. CrossRefPubMedGoogle Scholar
  71. 71.
    Rybka J, Kedziora-Kornatowska K, Banas-Lezanska P, Majsterek I, Carvalho LA, Cattaneo A, Anacker C, Kedziora J (2013) Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression. Free Radic Biol Med 63:187–194. CrossRefPubMedGoogle Scholar
  72. 72.
    Robaczewska J, Kedziora-Kornatowska K, Kucharski R, Nowak M, Muszalik M, Kornatowski M, Kedziora J (2016) Decreased expression of heme oxygenase is associated with depressive symptoms and may contribute to depressive and hypertensive comorbidity. Redox Rep 21(5):209–218. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Priscila B. Rosa
    • 1
  • Luis E. B. Bettio
    • 1
    • 2
  • Vivian B. Neis
    • 1
  • Morgana Moretti
    • 1
  • Isabel Werle
    • 1
  • Rodrigo B. Leal
    • 1
  • Ana Lúcia S. Rodrigues
    • 1
    Email author
  1. 1.Department of Biochemistry, Center of Biological SciencesUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Division of Medical SciencesUniversity of VictoriaVictoriaCanada

Personalised recommendations