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Vol. 17, No. 2, 2009
Issue release date: May 2009
Section title: Original Paper
Neurosignals 2009;17:162–168
(DOI:10.1159/000205525)

Nitric Oxide as an Upstream Signal of p38 Mediates Hypoxia/Reoxygenation-Induced Neuronal Death

Chen M.a · Sun H.-Y.b · Li S.-J.a · Das M.a · Kong J.-M.a, c · Gao T.-M.a
Departments of aAnatomy and Neurobiology, bPhysiology, Southern Medical University, Guangzhou, China; cDepartment of Human Anatomy and Cell Science, University of Manitoba, Faculty of Medicine, Winnipeg, Man., Canada
email Corresponding Author

Abstract

Nitric oxide (NO) and p38 have been shown to be involved in the ischemia/hypoxia-induced neuronal injury. In this study, we examined the activation patterns of mitogen-activated protein kinases and explored the relationship between NO and p38 in a model of hippocampal neuronal death induced by hypoxia/reoxygenation (H/R). p38 activity increased robustly during hypoxia and after reoxygenation, while the increase of c-Jun amino-terminal kinase and extracellular signal-related kinase activities showed mild tendency. Inhibition of p38 with SB203580 or SB202190 rescued neuronal death, whereas inhibition of extracellular signal-related kinases with PD98059 or c-Jun amino-terminal kinases with SP600125 offered no protection. p38 inhibitors also reduced neuronal death induced by the NO donor S-nitrosoglutathione. L-NAME, a nonspecific NO synthase inhibitor, blocked the p38 activation and rescued H/R-induced neuronal death. These results suggest that NO is an upstream signal of p38 that mediates the H/R-induced neuronal death.

© 2009 S. Karger AG, Basel


  

Key Words

  • Hypoxia
  • Hippocampal neuron
  • Cell death
  • Nitric oxide
  • Mitogen-activated protein kinase

References

  1. Haddad GG, Jiang C: O2 deprivation in the central nervous system: on mechanisms of neuronal response differential sensitivity and injury. Prog Neurobiol 1993;40:277–318.
  2. Mehta SL, Manhas N, Raghubir R: Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 2007;54:34–66.
  3. Szabo C: Physiological and pathophysiological roles of nitric oxide in the central nervous system. Brain Res Bull 1996;41:131–141.
  4. Lipton SA: Neuronal protection and destruction by NO. Cell Death Differ 1999;6:943–951.
  5. Tjong YW, Jian KH, Li M, Chen M, Gao TM, Fung ML: Elevated endogenous NO increases Ca2+ flux via L-type Ca2+ channels by S-nitrosylation in rat hippocampal neurons during severe hypoxia and in vitro ischemia. Free Radic Biol Med 2007;42:52–63.
  6. Jian KH, Chen M, Cao X, Zhu XH, Fung ML, Gao TM: Nitric oxide modulation of voltage-gated calcium current by S-nitrosylation and cGMP pathway in cultured rat hippocampal neurons. Biochem Biophys Res Commun 2007;359:481–485.
  7. Willmot M, Gray L, Gibson C, Murphy S, Bath PM: A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide 2005;12:141–149.
  8. Mungrue IN, Bredt DS: nNOS at a glance: implications for brain and brawn. J Cell Sci 2004;117:2627–2629.
  9. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA: Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994;265:1883–1885.
  10. Lipton P: Ischemic cell death in brain neurons. Physiol Rev 1999;79:1431–1568.
  11. Cowan KJ, Storey KB: Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol 2003;206:1107–1115.
  12. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326–1331.
  13. Ozawa H, Shioda S, Dohi K, Matsumoto H, Mizushima H, Zhou CJ, Funahashi H, Nakai Y, Nakajo S, Matsumoto K: Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 1999;262:57–60.
  14. Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, Nishida E: Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J Neurosci 2000;20:4506–4514.
  15. Li XM, Yang JM, Hu DH, Hou FQ, Zhao M, Zhu XH, Wang Y, Li JG, Hu P, Chen L, Qin LN, Gao TM: Contribution of down-regulation of L-type calcium currents to delayed neuronal death in rat hippocampus after global cerebral ischemia and reperfusion. J Neurosci 2007;27:5249–5259.
  16. Bossenmeyer C, Chihab R, Muller S, Schroeder H, Daval JL: Hypoxia/reoxygenation induces apoptosis through biphasic induction of protein synthesis in central neurons. Brain Res 1998;787:107–116.
  17. Ferrer I, Friguls B, Dalfo E, Planas AM: Early modification in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. Acta Neuropathol (Berl) 2003;105:425–437.
  18. Irving EA, Bamford M: Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 2002;22:631–647.
  19. Bossy-Wetzel E, Talantova MV, Lee WD, Scholzke MN, Harrop A, Mathews E, Gotz T, Han J, Ellisman MH, Perkins GA, Lipton SA: Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 2004;41:351–365.
  20. Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML, Courtney MJ: The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J Cell Biol 2005;168:117–126.
  21. Zhu Y, Mao XO, Sun Y, Xia Z, Greenberg DA: p38 mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. J Biol Chem 2002;277:22909–22914.
  22. Vartiainen N, Goldsteins G, Keksa-Goldsteine V, Chan PH, Koistinaho J: Aspirin inhibits p44/42 mitogen-activated protein kinase and is protective against hypoxia/reoxygenation neuronal damage. Stroke 2003;34:752–757.
  23. Okuno S, Saito A, Hayashi T, Chan PH: The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 2004;24:7879–7887.
  24. Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, Xia Z, Youle RJ, Morrison RS: p38 MAP kinase mediates Bax translocation in nitric oxide-induced apoptosis in neurons. J Cell Biol 2000;150:335–347.
  25. Schieke SM, Briviba K, Klotz L, Sies H: Activation pattern of mitogen-activated protein kinases elicited by peroxynitrite: attenuation by selenite supplementation. FEBS Lett 1999;448:301–303.
  26. Pyriochou A, Beis D, Koika V, Potytarchou C, Papadimitriou E, Zhou Z, Papapetropoulos A: Soluble guanylyl cyclase activation promotes angiogenesis. J Pharmacol Exp Ther 2006;319:663–671.

  

Author Contacts

Tian-Ming Gao, MD, PhD
Department of Anatomy and Neurobiology
Southern Medical University
Guangzhou 510515 (China)
Tel./Fax +86 20 6164 8216, E-Mail tgao@fimmu.com

  

Article Information

Received: April 22, 2008
Accepted after revision: June 24, 2008
Published online: March 4, 2009
Number of Print Pages : 7
Number of Figures : 5, Number of Tables : 0, Number of References : 26

  

Publication Details

Neurosignals

Vol. 17, No. 2, Year 2009 (Cover Date: May 2009)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


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References

  1. Haddad GG, Jiang C: O2 deprivation in the central nervous system: on mechanisms of neuronal response differential sensitivity and injury. Prog Neurobiol 1993;40:277–318.
  2. Mehta SL, Manhas N, Raghubir R: Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 2007;54:34–66.
  3. Szabo C: Physiological and pathophysiological roles of nitric oxide in the central nervous system. Brain Res Bull 1996;41:131–141.
  4. Lipton SA: Neuronal protection and destruction by NO. Cell Death Differ 1999;6:943–951.
  5. Tjong YW, Jian KH, Li M, Chen M, Gao TM, Fung ML: Elevated endogenous NO increases Ca2+ flux via L-type Ca2+ channels by S-nitrosylation in rat hippocampal neurons during severe hypoxia and in vitro ischemia. Free Radic Biol Med 2007;42:52–63.
  6. Jian KH, Chen M, Cao X, Zhu XH, Fung ML, Gao TM: Nitric oxide modulation of voltage-gated calcium current by S-nitrosylation and cGMP pathway in cultured rat hippocampal neurons. Biochem Biophys Res Commun 2007;359:481–485.
  7. Willmot M, Gray L, Gibson C, Murphy S, Bath PM: A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide 2005;12:141–149.
  8. Mungrue IN, Bredt DS: nNOS at a glance: implications for brain and brawn. J Cell Sci 2004;117:2627–2629.
  9. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA: Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994;265:1883–1885.
  10. Lipton P: Ischemic cell death in brain neurons. Physiol Rev 1999;79:1431–1568.
  11. Cowan KJ, Storey KB: Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. J Exp Biol 2003;206:1107–1115.
  12. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326–1331.
  13. Ozawa H, Shioda S, Dohi K, Matsumoto H, Mizushima H, Zhou CJ, Funahashi H, Nakai Y, Nakajo S, Matsumoto K: Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway. Neurosci Lett 1999;262:57–60.
  14. Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, Nishida E: Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J Neurosci 2000;20:4506–4514.
  15. Li XM, Yang JM, Hu DH, Hou FQ, Zhao M, Zhu XH, Wang Y, Li JG, Hu P, Chen L, Qin LN, Gao TM: Contribution of down-regulation of L-type calcium currents to delayed neuronal death in rat hippocampus after global cerebral ischemia and reperfusion. J Neurosci 2007;27:5249–5259.
  16. Bossenmeyer C, Chihab R, Muller S, Schroeder H, Daval JL: Hypoxia/reoxygenation induces apoptosis through biphasic induction of protein synthesis in central neurons. Brain Res 1998;787:107–116.
  17. Ferrer I, Friguls B, Dalfo E, Planas AM: Early modification in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. Acta Neuropathol (Berl) 2003;105:425–437.
  18. Irving EA, Bamford M: Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 2002;22:631–647.
  19. Bossy-Wetzel E, Talantova MV, Lee WD, Scholzke MN, Harrop A, Mathews E, Gotz T, Han J, Ellisman MH, Perkins GA, Lipton SA: Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 2004;41:351–365.
  20. Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML, Courtney MJ: The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J Cell Biol 2005;168:117–126.
  21. Zhu Y, Mao XO, Sun Y, Xia Z, Greenberg DA: p38 mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. J Biol Chem 2002;277:22909–22914.
  22. Vartiainen N, Goldsteins G, Keksa-Goldsteine V, Chan PH, Koistinaho J: Aspirin inhibits p44/42 mitogen-activated protein kinase and is protective against hypoxia/reoxygenation neuronal damage. Stroke 2003;34:752–757.
  23. Okuno S, Saito A, Hayashi T, Chan PH: The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 2004;24:7879–7887.
  24. Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, Xia Z, Youle RJ, Morrison RS: p38 MAP kinase mediates Bax translocation in nitric oxide-induced apoptosis in neurons. J Cell Biol 2000;150:335–347.
  25. Schieke SM, Briviba K, Klotz L, Sies H: Activation pattern of mitogen-activated protein kinases elicited by peroxynitrite: attenuation by selenite supplementation. FEBS Lett 1999;448:301–303.
  26. Pyriochou A, Beis D, Koika V, Potytarchou C, Papadimitriou E, Zhou Z, Papapetropoulos A: Soluble guanylyl cyclase activation promotes angiogenesis. J Pharmacol Exp Ther 2006;319:663–671.