Molecular Neurobiology

, Volume 53, Issue 1, pp 611–620 | Cite as

Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine

  • Carolina Gubert
  • Gabriel Rodrigo Fries
  • Bianca Pfaffenseller
  • Pâmela Ferrari
  • Robson Coutinho-Silva
  • Fernanda Bueno Morrone
  • Flávio Kapczinski
  • Ana Maria Oliveira Battastini


The objective of this study was to explore the association between the P2X7 purinergic receptor (P2X7R) and neuroinflammation using a preclinical model of acute bipolar mania. We analyzed the modulatory effects of P2X7R agonist (3′-O-(4-benzoyl)benzoyl-adenosine 5′-triphosphate, BzATP) and antagonists (brilliant blue, BBG and 3-[[5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride, A438079) on assessments related to behavior (locomotor activity), neuroinflammation (interleukin-1 beta, IL-1β; tumor necrosis factor alpha, TNF-α; and interleukin- 6, IL-6), oxidative stress (thiobarbituric acid reactive substances, TBARS) and neuroplasticity (brain-derived neurotrophic factor, BDNF) markers in a pharmacological model of mania induced by acute and chronic treatment with D-amphetamine (AMPH) (2 mg/kg) in mice. An apparent lack of responsiveness to AMPH was observed in terms of the locomotor activity in animals with blocked P2X7R or with genetic deletion of P2X7R in knockout (P2X7R−/−) mice. Likewise, P2X7R participated in the AMPH-induced increase of the proinflammatory and excitotoxic environment, as demonstrated by the reversal of IL-1β, TNF-α, and TBARS levels caused by P2X7R blocking. Our results support the hypothesis that P2X7R plays a role in the neuroinflammation induced by AMPH in a preclinical model of mania, which could explain the altered behavior. The present data suggest that P2X7R may be a therapeutic target related to the neuroinflammation reported in bipolar disorder.


Bipolar disorder P2X7 receptor D-amphetamine Neuroinflammation 



CG, GRF, and PF are recipients of scholarships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). BP is a scholarship recipient from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). This study was supported by the National Science and Technology Institute for Translational Medicine, funded by CNPq and by Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA).

Conflict of Interest

CG, GRF, BP, PF, RCS, and FBM declare no possible conflicts of interest, financial or otherwise, or grants or other forms of financial support. AMOB has received grant/research from CNPq. FK has received grant/research support from Astra-Zeneca, Eli Lilly, Janssen-Cilag, Servier, CNPq, CAPES, NARSAD, and the Stanley Medical Research Institute; has been a member of speakers boards for Astra-Zeneca, Eli Lilly, Janssen, and Servier; and has served as a consultant for Servier.


  1. 1.
    Kim YK, Jung HG, Myint AM, Kim H, Park SH (2007) Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord 104(1–3):91–95. doi: 10.1016/j.jad.2007.02.018 CrossRefPubMedGoogle Scholar
  2. 2.
    Rao JS, Harry GJ, Rapoport SI, Kim HW (2010) Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 15(4):384–392. doi: 10.1038/mp.2009.47 CrossRefPubMedGoogle Scholar
  3. 3.
    Ortiz-Domínguez A, Hernández ME, Berlanga C, Gutiérrez-Mora D, Moreno J, Heinze G, Pavón L (2007) Immune variations in bipolar disorder: phasic differences. Bipolar Disord 9(6):596–602. doi: 10.1111/j.1399-5618.2007.00493.x CrossRefPubMedGoogle Scholar
  4. 4.
    Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA (2010) The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 10(1):59–76. doi: 10.1586/ern.09.144 CrossRefPubMedGoogle Scholar
  5. 5.
    Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14(1):123–130. doi: 10.1017/S1461145710000805 CrossRefPubMedGoogle Scholar
  6. 6.
    Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Gonçalves CA, Santin A, Kapczinski F (2006) Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett 398(3):215–219. doi: 10.1016/j.neulet.2005.12.085 CrossRefPubMedGoogle Scholar
  7. 7.
    Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PV, Amminger P, McGorry P, Malhi GS (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35(3):804–817. doi: 10.1016/j.neubiorev.2010.10.001 CrossRefPubMedGoogle Scholar
  8. 8.
    Macêdo DS, Medeiros CD, Cordeiro RC, Sousa FC, Santos JV, Morais TA, Hyphantis TN, McIntyre RS, Quevedo J, Carvalho AF (2012) Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine. Bipolar Disord 14(7):707–718. doi: 10.1111/j.1399-5618.2012.01046.x CrossRefPubMedGoogle Scholar
  9. 9.
    Yates JW, Meij JT, Sullivan JR, Richtand NM, Yu L (2007) Bimodal effect of amphetamine on motor behaviors in C57BL/6 mice. Neurosci Lett 427(1):66–70. doi: 10.1016/j.neulet.2007.09.011 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Frey BN, Valvassori SS, Réus GZ, Martins MR, Petronilho FC, Bardini K, Dal-Pizzol F, Kapczinski F, Quevedo J (2006) Changes in antioxidant defense enzymes after d-amphetamine exposure: implications as an animal model of mania. Neurochem Res 31(5):699–703. doi: 10.1007/s11064-006-9070-6 CrossRefPubMedGoogle Scholar
  11. 11.
    Basso AM, Bratcher NA, Harris RR, Jarvis MF, Decker MW, Rueter LE (2009) Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders. Behav Brain Res 198(1):83–90. doi: 10.1016/j.bbr.2008.10.018 CrossRefPubMedGoogle Scholar
  12. 12.
    North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4):1013–1067. doi: 10.1152/physrev.00015.2002 CrossRefPubMedGoogle Scholar
  13. 13.
    Sun SH (2010) Roles of P2X7 receptor in glial and neuroblastoma cells: the therapeutic potential of P2X7 receptor antagonists. Mol Neurobiol 41(2–3):351–355. doi: 10.1007/s12035-010-8120-x CrossRefPubMedGoogle Scholar
  14. 14.
    Barden N, Harvey M, Gagné B, Shink E, Tremblay M, Raymond C, Labbé M, Villeneuve A, Rochette D, Bordeleau L, Stadler H, Holsboer F, Müller-Myhsok B (2006) Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 141B(4):374–382. doi: 10.1002/ajmg.b.30303 CrossRefPubMedGoogle Scholar
  15. 15.
    Bhattacharya A, Wang Q, Ao H, Shoblock JR, Lord B, Aluisio L, Fraser I, Nepomuceno D, Neff RA, Welty N, Lovenberg TW, Bonaventure P, Wickenden AD, Letavic MA (2013) Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567. Br J Pharmacol 170(3):624–640. doi: 10.1111/bph.12314 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gubert C, Rodrigo Fries G, Wollenhaupt de Aguiar B, Ribeiro Rosa A, Busnello JV, Ribeiro L, Bueno Morrone F, Oliveira Battastini AM, Kapczinski F (2013) The P2X7R purinergic receptor as a molecular target in bipolar disorder. Neuropsychiatr Neuropsychol 8(1):1Google Scholar
  17. 17.
    Csölle C, Andó RD, Kittel Á, Gölöncsér F, Baranyi M, Soproni K, Zelena D, Haller J, Németh T, Mócsai A, Sperlágh B (2013) The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice. Int J Neuropsychopharmacol 16(1):213–233. doi: 10.1017/S1461145711001933 CrossRefPubMedGoogle Scholar
  18. 18.
    NIH (2011) Guide for the care and use of laboratory animals—National Research Council 8th edn. The National Academies Press, Washington, DCGoogle Scholar
  19. 19.
    Engel T, Gomez-Villafuertes R, Tanaka K, Mesuret G, Sanz-Rodriguez A, Garcia-Huerta P, Miras-Portugal MT, Henshall DC, Diaz-Hernandez M (2012) Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice. FASEB J 26(4):1616–1628. doi: 10.1096/fj.11-196089 CrossRefPubMedGoogle Scholar
  20. 20.
    Frey BN, Andreazza AC, Ceresér KM, Martins MR, Petronilho FC, de Souza DF, Tramontina F, Gonçalves CA, Quevedo J, Kapczinski F (2006) Evidence of astrogliosis in rat hippocampus after D-amphetamine exposure. Prog Neuropsychopharmacol Biol Psychiatry 30(7):1231–1234. doi: 10.1016/j.pnpbp.2006.03.016 CrossRefPubMedGoogle Scholar
  21. 21.
    Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM (2013) Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med 19(6):773–777. doi: 10.1038/nm.3162 CrossRefPubMedGoogle Scholar
  22. 22.
    Maciel IS, Silva RB, Morrone FB, Calixto JB, Campos MM (2013) Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice. PLoS One 8(9):e77227. doi: 10.1371/journal.pone.0077227 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Loss CM, Córdova SD, de Oliveira DL (2012) Ketamine reduces neuronal degeneration and anxiety levels when administered during early life-induced status epilepticus in rats. Brain Res 1474:110–117. doi: 10.1016/j.brainres.2012.07.046 CrossRefPubMedGoogle Scholar
  24. 24.
    Gubert C, Stertz L, Pfaffenseller B, Panizzutti BS, Rezin GT, Massuda R, Streck EL, Gama CS, Kapczinski F, Kunz M (2013) Mitochondrial activity and oxidative stress markers in peripheral blood mononuclear cells of patients with bipolar disorder, schizophrenia, and healthy subjects. J Psychiatr Res 47(10):1396–1402. doi: 10.1016/j.jpsychires.2013.06.018 CrossRefPubMedGoogle Scholar
  25. 25.
    Barichello T, Generoso JS, Simões LR, Ceretta RA, Dominguini D, Ferrari P, Gubert C, Jornada LK, Budni J, Kapczinski F, Quevedo J (2014) Vitamin B6 prevents cognitive impairment in experimental pneumococcal meningitis. Exp Biol Med (Maywood). doi: 10.1177/1535370214535896 Google Scholar
  26. 26.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  27. 27.
    Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC, Plenk AM, Lowry MR, Richards RL, Carter C, Frech GC, Stone S, Rowe K, Chau CA, Cortado K, Hunt A, Luce K, O'Neil G, Poarch J, Potter J, Poulsen GH, Saxton H, Bernat-Sestak M, Thompson V, Gutin A, Skolnick MH, Shattuck D, Cannon-Albright L (2003) Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 73(6):1271–1281. doi: 10.1086/379978 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wilot LC, Bernardi A, Frozza RL, Marques AL, Cimarosti H, Salbego C, Rocha E, Battastini AM (2007) Lithium and valproate protect hippocampal slices against ATP-induced cell death. Neurochem Res 32(9):1539–1546. doi: 10.1007/s11064-007-9348-3 CrossRefPubMedGoogle Scholar
  29. 29.
    Melega WP, Williams AE, Schmitz DA, DiStefano EW, Cho AK (1995) Pharmacokinetic and pharmacodynamic analysis of the actions of D-amphetamine and D-methamphetamine on the dopamine terminal. J Pharmacol Exp Ther 274(1):90–96PubMedGoogle Scholar
  30. 30.
    Gonçalves J, Martins T, Ferreira R, Milhazes N, Borges F, Ribeiro CF, Malva JO, Macedo TR, Silva AP (2008) Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain. Ann N Y Acad Sci 1139:103–111. doi: 10.1196/annals.1432.043 CrossRefPubMedGoogle Scholar
  31. 31.
    Munkholm K, Braüner JV, Kessing LV, Vinberg M (2013) Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 47(9):1119–1133. doi: 10.1016/j.jpsychires.2013.05.018 CrossRefPubMedGoogle Scholar
  32. 32.
    Monif M, Burnstock G, Williams DA (2010) Microglia: proliferation and activation driven by the P2X7 receptor. Int J Biochem Cell Biol 42(11):1753–1756. doi: 10.1016/j.biocel.2010.06.021 CrossRefPubMedGoogle Scholar
  33. 33.
    Di Virgilio F (2007) Liaisons dangereuses: P2X(7) and the inflammasome. Trends Pharmacol Sci 28(9):465–472. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  34. 34.
    Skaper SD, Debetto P, Giusti P (2010) The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J 24(2):337–345. doi: 10.1096/fj.09-138883 CrossRefPubMedGoogle Scholar
  35. 35.
    Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F (2006) The P2X7 receptor: a key player in IL-1 processing and release. J Immunol 176(7):3877–3883CrossRefPubMedGoogle Scholar
  36. 36.
    Lucattelli M, Cicko S, Müller T, Lommatzsch M, De Cunto G, Cardini S, Sundas W, Grimm M, Zeiser R, Dürk T, Zissel G, Sorichter S, Ferrari D, Di Virgilio F, Virchow JC, Lungarella G, Idzko M (2011) P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema. Am J Respir Cell Mol Biol 44(3):423–429. doi: 10.1165/rcmb.2010-0038OC CrossRefPubMedGoogle Scholar
  37. 37.
    Sperlágh B, Vizi ES, Wirkner K, Illes P (2006) P2X7 receptors in the nervous system. Prog Neurobiol 78(6):327–346. doi: 10.1016/j.pneurobio.2006.03.007 CrossRefPubMedGoogle Scholar
  38. 38.
    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813(5):878–888. doi: 10.1016/j.bbamcr.2011.01.034 CrossRefPubMedGoogle Scholar
  39. 39.
    Ferrarese C, Beal MF (2004) Excitotoxicity in neurological diseases: New therapeutic challenge. Kluwer Academic Print, BostonGoogle Scholar
  40. 40.
    Blaylock R (2004) Excitotoxicity: a possible central mechanism in fluoride neurotoxicity. Fluoride 37(4):13Google Scholar
  41. 41.
    Frey BN, Martins MR, Petronilho FC, Dal-Pizzol F, Quevedo J, Kapczinski F (2006) Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania. Bipolar Disord 8(3):275–280. doi: 10.1111/j.1399-5618.2006.00318.x CrossRefPubMedGoogle Scholar
  42. 42.
    Steckert AV, Valvassori SS, Moretti M, Dal-Pizzol F, Quevedo J (2010) Role of oxidative stress in the pathophysiology of bipolar disorder. Neurochem Res 35(9):1295–1301. doi: 10.1007/s11064-010-0195-2 CrossRefPubMedGoogle Scholar
  43. 43.
    Martel-Gallegos G, Casas-Pruneda G, Ortega-Ortega F, Sánchez-Armass S, Olivares-Reyes JA, Diebold B, Pérez-Cornejo P, Arreola J (2013) Oxidative stress induced by P2X7 receptor stimulation in murine macrophages is mediated by c-Src/Pyk2 and ERK1/2. Biochim Biophys Acta 1830(10):4650–4659. doi: 10.1016/j.bbagen.2013.05.023 CrossRefPubMedGoogle Scholar
  44. 44.
    Apolloni S, Parisi C, Pesaresi MG, Rossi S, Carrì MT, Cozzolino M, Volonté C, D'Ambrosi N (2013) The NADPH oxidase pathway is dysregulated by the P2X7 receptor in the SOD1-G93A microglia model of amyotrophic lateral sclerosis. J Immunol 190(10):5187–5195. doi: 10.4049/jimmunol.1203262 CrossRefPubMedGoogle Scholar
  45. 45.
    Frey BN, Andreazza AC, Ceresér KM, Martins MR, Valvassori SS, Réus GZ, Quevedo J, Kapczinski F (2006) Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci 79(3):281–286. doi: 10.1016/j.lfs.2006.01.002 CrossRefPubMedGoogle Scholar
  46. 46.
    Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29(11):3518–3528. doi: 10.1523/JNEUROSCI. 5714-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155(7):1596–1609. doi: 10.1016/j.cell.2013.11.030 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Weitz TM, Town T (2012) Microglia in Alzheimer's disease: it's all about context. Int J Alzheimers Dis 2012:314185. doi: 10.1155/2012/314185 PubMedPubMedCentralGoogle Scholar
  49. 49.
    Bayer TA, Buslei R, Havas L, Falkai P (1999) Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 271(2):126–128CrossRefPubMedGoogle Scholar
  50. 50.
    Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J, Courchesne E, Everall IP (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 68(4):368–376. doi: 10.1016/j.biopsych.2010.05.024 CrossRefPubMedGoogle Scholar
  51. 51.
    Stertz L, Magalhães PV, Kapczinski F (2013) Is bipolar disorder an inflammatory condition? The relevance of microglial activation. Curr Opin Psychiatr 26(1):19–26. doi: 10.1097/YCO.0b013e32835aa4b4 CrossRefGoogle Scholar
  52. 52.
    Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39(1):3–18. doi: 10.1111/nan.12011 CrossRefPubMedGoogle Scholar
  53. 53.
    Cherry JD, Olschowka JA, O'Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98. doi: 10.1186/1742-2094-11-98 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    El-Mallakh RS, Decker S, Morris M, Li XP, Huff MO, El-Masri MA, Levy RS (2006) Efficacy of olanzapine and haloperidol in an animal model of mania. Prog Neuropsychopharmacol Biol Psychiatry 30(7):1261–1264. doi: 10.1016/j.pnpbp.2006.04.003 CrossRefPubMedGoogle Scholar
  55. 55.
    Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167(11):1305–1320. doi: 10.1176/appi.ajp.2009.10030434 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Frey BN, Valvassori SS, Réus GZ, Martins MR, Petronilho FC, Bardini K, Dal-Pizzol F, Kapczinski F, Quevedo J (2006) Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci 31(5):326–332PubMedPubMedCentralGoogle Scholar
  57. 57.
    Valvassori SS, Budni J, Varela RB, Quevedo J (2013) Contributions of animal models to the study of mood disorders. Rev Bras Psiquiatr 35(Suppl 2):S121–S131. doi: 10.1590/1516-4446-2013-1168 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Carolina Gubert
    • 1
    • 2
    • 3
  • Gabriel Rodrigo Fries
    • 2
    • 3
  • Bianca Pfaffenseller
    • 1
    • 2
    • 3
  • Pâmela Ferrari
    • 2
    • 3
    • 4
  • Robson Coutinho-Silva
    • 4
  • Fernanda Bueno Morrone
    • 5
  • Flávio Kapczinski
    • 2
    • 3
  • Ana Maria Oliveira Battastini
    • 1
    • 6
  1. 1.Programa de Pós-Graduação Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Bipolar Disorder Program and Laboratory of Molecular PsychiatryHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  3. 3.INCT of Translational MedicinePorto AlegreBrazil
  4. 4.Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  5. 5.Instituto de Toxicologia e Farmacologia, Faculdade de FarmáciaPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  6. 6.Departamento de BioquímicaInstituto de Ciências Básicas da SaúdePorto AlegreBrazil

Personalised recommendations