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Purinergic Signalling

, Volume 11, Issue 1, pp 117–126 | Cite as

Purine receptors are required for DHA-mediated neuroprotection against oxygen and glucose deprivation in hippocampal slices

  • Simone Molz
  • Gislaine Olescowicz
  • Jessica Rossana Kraus
  • Fabiana Kalyne Ludka
  • Carla I. Tasca
Original Article

Abstract

Docosahexaenoic acid (DHA) is important for central nervous system function during pathological states such as ischemia. DHA reduces neuronal injury in experimental brain ischemia; however, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on acute hippocampal slices subjected to experimental ischemia by transient oxygen and glucose deprivation (OGD) and re-oxygenation and the possible involvement of purinergic receptors as the mechanism underlying DHA-mediated neuroprotection. We observed that cellular viability reduction induced by experimental ischemia as well as cell damage and thiobarbituric acid reactive substances (TBARS) production induced by glutamate (10 mM) were prevented by hippocampal slices pretreated with DHA (5 μM). However, glutamate uptake reduction induced by OGD and re-oxygenation was not prevented by DHA. The beneficial effect of DHA against cellular viability reduction induced by OGD and re-oxygenation was blocked with PPADS (3 μM), a nonselective P2X1–5 receptor antagonist as well as with a combination of TNP-APT (100 nM) plus brilliant blue (100 nM), which blocked P2X1, P2X3, P2X2/3, and P2X7 receptors, respectively. Moreover, adenosine receptors blockade with A1 receptor antagonist DPCPX (100 nM) or with A2B receptor antagonist alloxazine (100 nM) inhibited DHA-mediated neuroprotection. The addition of an A2A receptor antagonist ZM241385 (50 nM), or A3 receptor antagonist VUF5574 (1 μM) was ineffective. Taken together, our results indicated that neuroprotective actions of DHA may depend on P2X, A1, and A2B purinergic receptors activation. Our results reinforce the notion that dietary DHA may act as a local purinergic modulator in order to prevent neurodegenerative diseases.

Keywords

DHA Adenosine receptors ATP receptors Neuroprotection 

Notes

Acknowledgments

This study and FKL were supported by grants from Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC). GO was supported by Fundo de Apoio à Manutenção e ao Desenvolvimento da Educação Superior (FUMDES). C.I.T. is recipient of CNPq productivity fellowship. The authors thank the Universidade do Contestado for the animal house facility.

Conflict of interest

The authors state that there is no conflict of interest.

References

  1. 1.
    Amadio S, D’Ambrosi N, Cavaliere F, Murra B, Sancesario G, Bernardi G, Burnstock G, Volonte C (2002) P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology 42:489–501CrossRefPubMedGoogle Scholar
  2. 2.
    Arias RL, Tasse JR, Bowlby MR (1999) Neuroprotective interaction effects of NMDA and AMPA receptor antagonists in an in vitro model of cerebral ischemia. Brain Res 816:299–308CrossRefPubMedGoogle Scholar
  3. 3.
    Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s, and other neurodegenerative diseases. Annu Rev Nutr 31:321–351CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Bazan NG, Musto AE, Knott EJ (2011) Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity. Mol Neurobiol 44:216–222CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Begum G, Kintner D, Liu Y, Cramer SW, Sun D (2012) DHA inhibits ER Ca2+ release and ER stress in astrocytes following in vitro ischemia. J Neurochem 120:622–630CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Belayev L, Khoutorova L, Atkins KD, Eady TN, Hong S, Lu Y, Obenaus A, Bazan NG (2011) Docosahexaenoic acid therapy of experimental ischemic stroke. Transl Stroke Res 2:33–41CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Boison D (2009) Adenosine augmentation therapies (AATs) for epilepsy: prospect of cell and gene therapies. Epilepsy Res 85:131–141CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Brenna JT, Salem N Jr, Sinclair AJ, Cunnane SC (2009) Alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot Essent Fat Acids 80:85–91CrossRefGoogle Scholar
  9. 9.
    Brongholi K, Souza DG, Bainy AC, Dafre AL, Tasca CI (2006) Oxygen-glucose deprivation decreases glutathione levels and glutamate uptake in rat hippocampal slices. Brain Res 1083:211–218CrossRefPubMedGoogle Scholar
  10. 10.
    Brown P, Dale N (2000) Adenosine A1 receptors modulate high voltage-activated Ca2+ currents and motor pattern generation in the Xenopus embryo. J Physiol 525(Pt 3):655–667CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Burnstock G (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64:1471–1483CrossRefPubMedGoogle Scholar
  12. 12.
    Burnstock G, Krugel U, Abbracchio MP, Illes P (2011) Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol 95:229–274CrossRefPubMedGoogle Scholar
  13. 13.
    Calon F, Cole G (2007) Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fat Acids 77:287–293CrossRefGoogle Scholar
  14. 14.
    Carmo MR, Simoes AP, Fonteles AA, Souza CM, Cunha RA, Andrade GM (2014) ATP P2Y1 receptors control cognitive deficits and neurotoxicity but not glial modifications induced by brain ischemia in mice. Eur J Neurosci 39:614–622CrossRefPubMedGoogle Scholar
  15. 15.
    Cavaliere F, Florenzano F, Amadio S, Fusco FR, Viscomi MT, D’Ambrosi N, Vacca F, Sancesario G, Bernardi G, Molinari M, Volontà C (2003) Up-regulation of P2X2, P2X4 receptor and ischemic cell death: prevention by P2 antagonists. Neuroscience 120:85–98CrossRefPubMedGoogle Scholar
  16. 16.
    Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14:1490–1499CrossRefPubMedGoogle Scholar
  17. 17.
    Choi D (1998) Antagonizing excitotoxicity: a therapeutic strategy for stroke? Mt Sinai J Med 65:133–138PubMedGoogle Scholar
  18. 18.
    Chu S, Xiong W, Zhang D, Soylu H, Sun C, Albensi BC, Parkinson FE (2013) Regulation of adenosine levels during cerebral ischemia. Acta Pharmacol Sin 34:60–66CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Cunha RA (2001) Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 38:107–125CrossRefPubMedGoogle Scholar
  20. 20.
    Cunha RA (2005) Neuroprotection by adenosine in the brain: from A(1) receptor activation to A (2A) receptor blockade. Purinergic Signal 1:111–134CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Cunha RA, Almeida T, Ribeiro JA (2000) Modification by arachidonic acid of extracellular adenosine metabolism and neuromodulatory action in the rat hippocampus. J Biol Chem 275:37572–37581CrossRefPubMedGoogle Scholar
  22. 22.
    Dale N, Frenguelli BG (2009) Release of adenosine and ATP during ischemia and epilepsy. Curr Neuropharmacol 7:160–179CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105CrossRefPubMedGoogle Scholar
  24. 24.
    Denis I, Potier B, Vancassel S, Heberden C, Lavialle M (2013) Omega-3 fatty acids and brain resistance to ageing and stress: body of evidence and possible mechanisms. Ageing Res Rev 12:579–594CrossRefPubMedGoogle Scholar
  25. 25.
    Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009) Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 32:79–87CrossRefPubMedGoogle Scholar
  26. 26.
    Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55CrossRefPubMedGoogle Scholar
  27. 27.
    Eady TN, Khoutorova L, Anzola DV, Hong SH, Obenaus A, Mohd-Yusof A, Bazan NG, Belayev L (2013) Acute treatment with docosahexaenoic acid complexed to albumin reduces injury after a permanent focal cerebral ischemia in rats. PLoS ONE 8:e77237CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Eto K, Arimura Y, Mizuguchi H, Nishikawa M, Noda M, Ishibashi H (2006) Modulation of ATP-induced inward currents by docosahexaenoic acid and other fatty acids in rat nodose ganglion neurons. J Pharmacol Sci 102:343–346CrossRefPubMedGoogle Scholar
  29. 29.
    Farooqui AA, Horrocks LA (2001) Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue. J Mol Neurosci 16:263–272, discussion 279–84CrossRefPubMedGoogle Scholar
  30. 30.
    Fedalto ML, Ludka FK, Tasca CI, Molz S (2013) Neuroprotection of Persea major extract against oxygen and glucose deprivation in hippocampal slices involves increased glutamate uptake and modulation of A1 and A2A adenosine receptors. Rev Bras Farmacognosia 23:789–795CrossRefGoogle Scholar
  31. 31.
    Franke H, Krugel U, Illes P (2006) P2 receptors and neuronal injury. Pflugers Arch 452:622–644CrossRefPubMedGoogle Scholar
  32. 32.
    Franke H, Verkhratsky A, Burnstock G, Illes P (2012) Pathophysiology of astroglial purinergic signalling. Purinergic Signal 8:629–657CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323CrossRefPubMedGoogle Scholar
  34. 34.
    Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM (2005) Adenosine and brain function. Int Rev Neurobiol 63:191–270CrossRefPubMedGoogle Scholar
  35. 35.
    Fredholm BB, Irenius E, Kull B, Schulte G (2001) Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61:443–448CrossRefPubMedGoogle Scholar
  36. 36.
    Grintal B, Champeil-Potokar G, Lavialle M, Vancassel S, Breton S, Denis I (2009) Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signalling role of docosahexaenoic acid. Neurochem Int 54:535–543CrossRefPubMedGoogle Scholar
  37. 37.
    Jiang LH, Mackenzie AB, North RA, Surprenant A (2000) Brilliant blue G selectively blocks ATP-gated rat P2X(7) receptors. Mol Pharmacol 58:82–88PubMedGoogle Scholar
  38. 38.
    Khakh BS (2001) Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci 2:165–174CrossRefPubMedGoogle Scholar
  39. 39.
    Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC, Stebbins JL, Pellecchia M, Sarkar D, Fisher PB (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226:2484–2493CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Lopes LV, Sebastiao AM, Ribeiro JA (2011) Adenosine and related drugs in brain diseases: present and future in clinical trials. Curr Top Med Chem 11:1087–1101CrossRefPubMedGoogle Scholar
  41. 41.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  42. 42.
    Mahe G, Ronziere T, Laviolle B, Golfier V, Cochery T, De Bray JM, Paillard F (2010) An unfavorable dietary pattern is associated with symptomatic ischemic stroke and carotid atherosclerosis. J Vasc Surg 52:62–68CrossRefPubMedGoogle Scholar
  43. 43.
    Mayurasakorn K, Williams JJ, Ten VS, Deckelbaum RJ (2011) Docosahexaenoic acid: brain accretion and roles in neuroprotection after brain hypoxia and ischemia. Curr Opin Clin Nutr Metab Care 14:158–167CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Menard C, Patenaude C, Gagne AM, Massicotte G (2009) AMPA receptor-mediated cell death is reduced by docosahexaenoic acid but not by eicosapentaenoic acid in area CA1 of hippocampal slice cultures. J Neurosci Res 87:876–886CrossRefPubMedGoogle Scholar
  45. 45.
    Miyagawa N, Miura K, Okuda N, Kadowaki T, Takashima N, Nagasawa SY, Nakamura Y, Matsumura Y, Hozawa A, Fujiyoshi A, Hisamatsu T, Yoshita K, Sekikawa A, Ohkubo T, Abbott RD, Okamura T, Okayama A, Ueshima H (2014) Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80. Atherosclerosis 232:384–389CrossRefPubMedGoogle Scholar
  46. 46.
    Moidunny S, Vinet J, Wesseling E, Bijzet J, Shieh CH, van Ijzendoorn SC, Bezzi P, Boddeke HW, Biber K (2012) Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity. J Neuroinflammation 9:198CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Molz S, Dal-Cim T, Tasca CI (2009) Guanosine-5′-monophosphate induces cell death in rat hippocampal slices via ionotropic glutamate receptors activation and glutamate uptake inhibition. Neurochem Int 55:703–709CrossRefPubMedGoogle Scholar
  48. 48.
    Molz S, Decker H, Dal-Cim T, Cremonez C, Cordova FM, Leal RB, Tasca CI (2008) Glutamate-induced toxicity in hippocampal slices involves apoptotic features and p38 MAPK signaling. Neurochem Res 33:27–36CrossRefPubMedGoogle Scholar
  49. 49.
    Moreira JD, Knorr L, Thomazi AP, Simao F, Battu C, Oses JP, Gottfried C, Wofchuk S, Salbego C, Souza DO, Perry ML, Vinade L (2009) Dietary omega-3 fatty acids attenuate cellular damage after a hippocampal ischemic insult in adult rats. J Nutr Biochem 21:351–356CrossRefPubMedGoogle Scholar
  50. 50.
    Mori TA (2014) Omega-3 fatty acids and cardiovascular disease: epidemiology and effects on cardiometabolic risk factors. Food Funct 5:2004–2019CrossRefPubMedGoogle Scholar
  51. 51.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  52. 52.
    Nagan N, Zoeller RA (2001) Plasmalogens: biosynthesis and functions. Prog Lipid Res 40:199–229CrossRefPubMedGoogle Scholar
  53. 53.
    Nishikawa M, Kimura S, Akaike N (1994) Facilitatory effect of docosahexaenoic acid on N-methyl-D-aspartate response in pyramidal neurones of rat cerebral cortex. J Physiol 475:83–93CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefPubMedGoogle Scholar
  55. 55.
    Oleskovicz SP, Martins WC, Leal RB, Tasca CI (2008) Mechanism of guanosine-induced neuroprotection in rat hippocampal slices submitted to oxygen-glucose deprivation. Neurochem Int 52:411–418CrossRefPubMedGoogle Scholar
  56. 56.
    Oliveira IJ, Molz S, Souza DO, Tasca CI (2002) Neuroprotective effect of GMP in hippocampal slices submitted to an in vitro model of ischemia. Cell Mol Neurobiol 22:335–344CrossRefPubMedGoogle Scholar
  57. 57.
    Pedata F, Melani A, Pugliese AM, Coppi E, Cipriani S, Traini C (2007) The role of ATP and adenosine in the brain under normoxic and ischemic conditions. Purinergic Signal 3:299–310CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Phillis JW, O’Regan MH (2004) A potentially critical role of phospholipases in central nervous system ischemic, traumatic, and neurodegenerative disorders. Brain Res Brain Res Rev 44:13–47CrossRefPubMedGoogle Scholar
  59. 59.
    Pugliese AM, Coppi E, Spalluto G, Corradetti R, Pedata F (2006) A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro. Br J Pharmacol 147:524–532CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Rapoport SI, Rao JS, Igarashi M (2007) Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fat Acids 77:251–261CrossRefGoogle Scholar
  61. 61.
    Rebola N, Pinheiro PC, Oliveira CR, Malva JO, Cunha RA (2003) Subcellular localization of adenosine A(1) receptors in nerve terminals and synapses of the rat hippocampus. Brain Res 987:49–58CrossRefPubMedGoogle Scholar
  62. 62.
    Rodrigues RJ, Almeida T, Richardson PJ, Oliveira CR, Cunha RA (2005) Dual presynaptic control by ATP of glutamate release via facilitatory P2X1, P2X2/3, and P2X3 and inhibitory P2Y1, P2Y2, and/or P2Y4 receptors in the rat hippocampus. J Neurosci 25:6286–6295CrossRefPubMedGoogle Scholar
  63. 63.
    Saremi A, Arora R (2009) The utility of omega-3 fatty acids in cardiovascular disease. Am J Ther 16:421–436CrossRefPubMedGoogle Scholar
  64. 64.
    Sergeeva M, Strokin M, Reiser G (2005) Regulation of intracellular calcium levels by polyunsaturated fatty acids, arachidonic acid and docosahexaenoic acid, in astrocytes: possible involvement of phospholipase A2. Reprod Nutr Dev 45:633–646CrossRefPubMedGoogle Scholar
  65. 65.
    Sheng H, Li P, Chen X, Liu B, Zhu Z, Cao W (2014) Omega-3 PUFAs induce apoptosis of gastric cancer cells via ADORA1. Front Biosci (Landmark Ed) 19:854–861CrossRefGoogle Scholar
  66. 66.
    Sperlagh B, Vizi ES (2011) The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: pharmacological and clinical aspects. Curr Top Med Chem 11:1034–1046CrossRefPubMedCentralPubMedGoogle Scholar
  67. 67.
    Stone TW, Ceruti S,Abbracchio MP (2009) Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handb Exp Pharmacol 535–87Google Scholar
  68. 68.
    Strasser U, Fischer G (1995) Protection from neuronal damage induced by combined oxygen and glucose deprivation in organotypic hippocampal cultures by glutamate receptor antagonists. Brain Res 687:167–174CrossRefPubMedGoogle Scholar
  69. 69.
    Strokin M, Chechneva O, Reymann KG, Reiser G (2006) Neuroprotection of rat hippocampal slices exposed to oxygen-glucose deprivation by enrichment with docosahexaenoic acid and by inhibition of hydrolysis of docosahexaenoic acid-containing phospholipids by calcium independent phospholipase A2. Neuroscience 140:547–553CrossRefPubMedGoogle Scholar
  70. 70.
    Strokin M, Sergeeva M, Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 139:1014–1022CrossRefPubMedCentralPubMedGoogle Scholar
  71. 71.
    Taha AY, Jeffrey MA, Taha NM, Bala S, Burnham WM (2010) Acute administration of docosahexaenoic acid increases resistance to pentylenetetrazol-induced seizures in rats. Epilepsy Behav 17:336–343CrossRefPubMedGoogle Scholar
  72. 72.
    Tetzlaff W, Schubert P, Kreutzberg GW (1987) Synaptic and extrasynaptic localization of adenosine binding sites in the rat hippocampus. Neuroscience 21:869–875CrossRefPubMedGoogle Scholar
  73. 73.
    Thrift AG, Cadilhac DA, Thayabaranathan T, Howard G, Howard VJ, Rothwell PM, Donnan GA (2014) Global stroke statistics. Int J Stroke 9:6–18CrossRefPubMedGoogle Scholar
  74. 74.
    Trotti D, Danbolt NC, Volterra A (1998) Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci 19:328–334CrossRefPubMedGoogle Scholar
  75. 75.
    von Lubitz DK, Ye W, McClellan J, Lin RC (1999) Stimulation of adenosine A3 receptors in cerebral ischemia. Neuronal death, recovery, or both? Ann N Y Acad Sci 890:93–106CrossRefGoogle Scholar
  76. 76.
    Wang X, Zhao X, Mao ZY, Wang XM, Liu ZL (2003) Neuroprotective effect of docosahexaenoic acid on glutamate-induced cytotoxicity in rat hippocampal cultures. Neuroreport 14:2457–2461CrossRefPubMedGoogle Scholar
  77. 77.
    Wei JW, Wang JG, Huang Y, Liu M, Wu Y, Wong LK, Cheng Y, Xu E, Yang Q, Arima H, Heeley EL, Anderson CS (2010) Secondary prevention of ischemic stroke in urban China. Stroke 41:967–974CrossRefPubMedGoogle Scholar
  78. 78.
    Wilding TJ, Chai YH, Huettner JE (1998) Inhibition of rat neuronal kainate receptors by cis-unsaturated fatty acids. J Physiol 513(Pt 2):331–339CrossRefPubMedCentralPubMedGoogle Scholar
  79. 79.
    Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364:937–952CrossRefPubMedGoogle Scholar
  80. 80.
    Zhang M, Wang S, Mao L, Leak RK, Shi Y, Zhang W, Hu X, Sun B, Cao G, Gao Y, Xu Y, Chen J, Zhang F (2014) Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1. J Neurosci 34:1903–1915CrossRefPubMedCentralPubMedGoogle Scholar
  81. 81.
    Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedeberg’s Arch Pharmacol 362:299–309CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Simone Molz
    • 1
  • Gislaine Olescowicz
    • 1
  • Jessica Rossana Kraus
    • 1
  • Fabiana Kalyne Ludka
    • 1
    • 3
  • Carla I. Tasca
    • 2
    • 3
  1. 1.Curso de FarmáciaUniversidade do Contestado (UnC)CanoinhasBrazil
  2. 2.Departamento de Bioquímica, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  3. 3.Programa de Pós-graduação em Bioquímica, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil

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