Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death

Abstract

Glutamate is the main excitatory neurotransmitter in mammals. However, excessive activation of glutamate receptors is neurotoxic, leading to neuronal degeneration and death. In many systems, including primary cultures of cerebellar neurons, glutamate neurotoxicity is mainly mediated by excessive activation of NMDA receptors, leading to increased intracellular calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS), increasing nitric oxide (NO) which in turn activates guanylate cyclase and increases cGMP. Inhibition of NOS prevents glutamate neurotoxicity, indicating that NO mediates glutamate-induced neuronal death in this system. NO generating agents such as SNAP also induce neuronal death. Compounds that can act as “scavengers” of NO such as Croman 6 (CR-6) prevent glutamate neurotoxicity.

The role of cGMP in the mediation of glutamate neurotoxicity remain controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and NO neurotoxicity in cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and NO neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase increased extracellular but not intracellular cGMP and prevented glutamate neurotoxicity. Addition of cGMP to the medium also prevented glutamate neurotoxicity. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.

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Reference

  1. Appel, S.H. Excitotoxic neuronal cell death in amyotrophic lateral sclerosis.TiNS,16: 3–4.

  2. Blandini, F., Porter, R.H. and Greenamyre, J.T. (1996) Glutamate and Parkinson’s disease.Mol Neurobiol 12: 73–94.

    PubMed  Article  CAS  Google Scholar 

  3. Bonfoco, E., Leist, M., Zhivotovsky, B., Orrenius, S., Lipton, S.A. and Nicotera, P. (1996) Cytoskeletal breakdown and apoptosis elicited by NO donors in cerebellar granule cells require NMDA receptor activation.J. Neurochem. 67, 2484–2493.

    PubMed  CAS  Google Scholar 

  4. Borutaite, V. and Brown, G.C. (1996) Rapid reduction of nitric oxide by mitochondria, and reversible inhibition of respiration by nitric oxide.Biochem. J. 315, 295–299.

    PubMed  CAS  Google Scholar 

  5. Brorson, J.R. and Zhang, H. (1997) Disrupted Ca homeostasis contributes to the toxicity of nitric oxide in cultured hippocampal neurons.J. Neurochem. 69, 1882–1889.

    PubMed  CAS  Google Scholar 

  6. Cazevieille, C, Muller, A., Meynier, F. and Bonne, C. (1993) Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury.Free Rad Biol Med. 14: 389–395.

    PubMed  Article  CAS  Google Scholar 

  7. Choi, D.W. (1987) Ionic dependence of glutamate neurotoxicity.J. Neurosci. 7: 369–379.

    PubMed  CAS  Google Scholar 

  8. Cucarella, C, Montoliu, C, Hermenegildo, C., Saez, R., Manzo, L., Miñana, M. D. and Felipo, V. (1998) Chronic exposure to aluminium impairs neuronal glutamate-nitric oxide-cyclic GMP pathway.J. Neurochem. 70, 1609–1614.

    PubMed  CAS  Google Scholar 

  9. Dawson, V.L., Dawson, T.M., London, E.D. and Bredt, D.S. (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.Proc. Natl. Acad. Sci USA 88, 6368–6371.

    PubMed  Article  CAS  Google Scholar 

  10. Dawson, V.L., Dawson, T., Bartley, D. A., Uhl, G.R., and Snyder, S.H. (1993) Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures.J. Neurosci. 13: 2651–2661.

    PubMed  CAS  Google Scholar 

  11. Dawson, T.M., Steiner, J.P., Dawson, V.L., Dinerman, J.L., Uhl, G.R. and Snyder, S. (1993b) Immunosuppresant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity.Proc. Natl. Acad. Sci USA 90, 9808–9812.

    PubMed  Article  CAS  Google Scholar 

  12. Dawson, V.L., Kizushi, V.M., Huang, P.L., Snyder, S. and Dawson, T.M. (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice.J. Neurosci. 16, 2479–2487.

    PubMed  CAS  Google Scholar 

  13. Felipo, V., Miftana, M. D. and Grisolia, S. (1993) Inhibitors of protein kinase C prevent the toxicity of glutamate in primary neuronal cultures.Brain Res. 604, 192–196.

    PubMed  Article  CAS  Google Scholar 

  14. Forloni, G., Lucca, E., Angeretti, N., Chiesa, R. and Vezzani, A. (1997) Neuroprotective effect of somatostatin on non-apoptotic NMDA-induced neuronal death: role of cyclic GMP.J. Neurochem. 68: 319–327.

    PubMed  CAS  Article  Google Scholar 

  15. Frandsen, A., Andersen, C. F. and Schousboe, A. (1992) Possible role of cGMP in excitatory amino acid induced cytotoxicity in cultured cerebral cortical neurons.Neurochem. Res. 17: 35–43.

    PubMed  Article  CAS  Google Scholar 

  16. Ghafourifar, P, Schenk, U., Klein, S.D. and Richter, C. (1999) Mitochondrial nitric oxide synthase stimulation causes cytochrome c release from mitochondria. Evidence for intramitochondrial peroxynitrite formation.J. Biol. Chem. 274, 31185–31188.

    PubMed  Article  CAS  Google Scholar 

  17. Garthwaite, G. and Garthwaite, J. (1988) Cyclic GMP and cell death in rat cerebellar slices.Neuroscience 26: 321–326.

    PubMed  Article  CAS  Google Scholar 

  18. Gunasekar, P.G., Kanthasamy, A.G., Borowitz, J.L. and Isom, G.E. (1995) NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implications for cell death.J. Neurochem. 65, 2016–2021.

    PubMed  CAS  Google Scholar 

  19. Hammer, B., Parkeer, W.D., and Bennet, J.P. (1993) NMDA receptors increase OH radicals in vivo by using nitric oxide synthase and protein kinase C.NeuroReport 5, 72–74.

    PubMed  Article  CAS  Google Scholar 

  20. Hermenegildo, C, Montoliu, C, Llansola, M., Mufioz, M.D., Gaztelu, J.M., Miflana, M. D. and Felipo, V. (1998) Chronic hyperammonemia impairs glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.Eur. J. Neurosci. 10: 3201–3209.

    PubMed  Article  CAS  Google Scholar 

  21. Gonzalez-Zulueta, M., Ensz, L.M., Mukhina, G., Lebovitz, R.M., Zwacka, R.M., Engelhardt, J.F., Oberley, L.W., Dawson, V.L. and Dawson, T.M. (1998) Manganese superoxide dismutase protects nNOS neurons from NMDA and nitric oxide-mediated neurotoxicity.J. Neurosci. 18, 2040–2055.

    PubMed  CAS  Google Scholar 

  22. Hortelano S, Alvarez AM, Bosca L (1999); Nitric oxide induces tyrosine nitration and release of cytochrome c preceding an increase of mitochondrial transmembrane potential in macrophages.FASEB J 13: 2311–7.

    PubMed  CAS  Google Scholar 

  23. Izumi, Y., Benz, A.M., Clifford, D.B. and Zorumski, C.F. (1992) Nitric oxide inhibitors attenuate N-methyl-D-aspartate excitotoxicity in rat hippocampal slices.Neurosci Lett 135, 227–230.

    PubMed  Article  CAS  Google Scholar 

  24. Kollegger, H., McBean, G.J. and Tipton, K.F. (1993) Reduction of striatal N-methyl-D-aspartate toxicity by inhibition of nitric oxide synthase.Biochem. Pharmacol. 45, 260–264.

    PubMed  Article  CAS  Google Scholar 

  25. Kume, T., Kouchiyama, H., Kaneko, S., Maeda, T., Kaneko, S., Akaike, A., Shimohama, S., Kihara, J., Wada, K. And Koizumi, S. (1997) BDNF prevents NO mediated glutamate cytotoxicity in cultured cortical neurons.Brain Res. 756, 200–204.

    PubMed  Article  CAS  Google Scholar 

  26. Lafon-Cazal, M., Culcasi, M., Gaven, F., Pietri, S. and Bockaert, J. (1993) Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells.Neuropharmacology 32: 1259–1266.

    PubMed  Article  CAS  Google Scholar 

  27. Li, Y., Maher, P. and Schubert, D. (1997) Requirement for cGMP in nerve cell death caused by glutathione depletion.J. Cell. Biol. 139: 1317–1324.

    PubMed  Article  CAS  Google Scholar 

  28. Lolley, R.N., Farber, D.B., Rayborn, M. E., and Hollyfield, J. G. (1977) Cyclic GMP accumulation causes degeneration of photoreceptor cells: Simulation of an inherited disease.Science 196: 664–666.

    PubMed  Article  CAS  Google Scholar 

  29. Maiese, K., Boniece, I.R., Skurat, K. and Wagner, J.A. (1993) Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia.J. Neurosci Res. 36: 77–87.

    PubMed  Article  CAS  Google Scholar 

  30. Malcolm, C. S., Ritchie, L., Grieve, A. and Griffiths, R. (1996) Glutamate toxicity in primary cerebellar cultures from mouse brain is unaffected by changes in cGMP levels.NeuroReport 7: 1650–1654.

    PubMed  Article  CAS  Google Scholar 

  31. Manev, H., Favaron, M., Guidotti, A. and Costa, E. (1989) Delayed increase of Ca influx elicited by glutamate: Role in neuronal death.Mol. Pharmacol. 36: 106–112.

    PubMed  CAS  Google Scholar 

  32. Maragos, W.F., Greenamyre, J.T., Penney, J.B. and Young, A. B. (1987) Glutamate dysfunction in Alzheimer’s disease: an hypothesis.TiNS 10: 65–68.

    CAS  Google Scholar 

  33. Marcaida, G., Miftana, M. D., Grisolia, S. and Felipo, V. (1995) Lack of correlation between glutamate-induced depletion of ATP and neuronal death in primary cultures of cerebellum. Brain Res.695, 146–150.

    PubMed  Article  CAS  Google Scholar 

  34. Martin, L.J., Price, A.C., Kaiser, A., Shaikh, A.Y. and Liu, Z. (2000). Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death.Int. J. Mol. Med. 5: 3–13.

    PubMed  CAS  Google Scholar 

  35. Masliah, E., Alford, M., DeTeresa, R., Mallory, M. and Hansen, L. (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease.Ann Neurol 40: 759–766.

    PubMed  Article  CAS  Google Scholar 

  36. Miftana, M. D., Hermenegildo, C, Llansola, M., Montoliu, C, Grisolia, S. and Felipo, V. (1996) Carnitine and choline derivetives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons.J. Pharmacol. Exp. Ther. 279: 194–199.

    Google Scholar 

  37. Miftana, M. D., Montoliu, C, Llansola, M., Grisolia, S. and Felipo, V. (1998) Nicotine prevents glutamate-induced proteolysis of the microtubule-associated protein MAP-2 and glutamate neurotoxicity in primary cultures of cerebellar neurons.Neuropharmacol. 37: 847–857.

    Article  Google Scholar 

  38. Montoliu, C, Llansola, M, Saez, R, Yenes, S, Messeguer, A and Felipo, V. Prevention of glutamate neurotoxicity in cultured neurons by 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-l(2h)-benzopyran (CR-6), an scavenger of nitric oxide. (1999a). Biochem. Pharmacol.58, 255–261.

    PubMed  Article  CAS  Google Scholar 

  39. Montoliu, C., Llansola, M., Kosenko, E., Corbalan, R., Felipo, V. Role of cyclic GMP in glutamate neurotoxicity in primary cultures of cerebellar neurons. (1999b) Neuropharmacology38, 1883–1891.

    PubMed  Article  CAS  Google Scholar 

  40. Olney, J.W., Wozniak, D. F. and Farber, N.B. (1997) Excitotoxic neurodegeneration in Alzheimer disease.Arch. Neurol. 54: 1234–1240.

    PubMed  CAS  Google Scholar 

  41. Poderoso, J.J., Carreras, M.C., Lisdero, C, Riobo, N., Schopfer, N. and Boveris, A. (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in mitochondria and submitochondrial particles.Arch Biochim Biophys 328, 85–92.

    Article  CAS  Google Scholar 

  42. Reif, D.W. (1993) Delayed production of nitric oxide contributes to NMDA-mediated neuronal damage.NeuroReport 4, 566–568.

    PubMed  Article  CAS  Google Scholar 

  43. Reynolds, G.P. and Pearson, S.J. (1994) Glutamate in Huntington’s disease.Lancet 344: 189–190.

    PubMed  Article  CAS  Google Scholar 

  44. Skaper, S.D., Ancona, B., Facci, L., Franceschini, D. and Giusti, P. (1998) Melatonin prevents the delayed death of hippocampal neurons induced by enhanced excitatory neurotransmission and the nitridergic pathway.FASEB J. 12, 725–731.

    PubMed  CAS  Google Scholar 

  45. Strijbos, P.J.L.M., Leach, M.J. and Garthwaite, J. (1996) Vicious cycle involving Na+ channels, glutamate release, and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation.J. Neurosci. 16, 5004–5013.

    PubMed  CAS  Google Scholar 

  46. Taylor-Robinson, S.D., Weeks, R.A., Sargentoni, J., Marcus, CD., Bryant, D.G., Harding, A.E., Brooks, W. (1994) Evidence for glutamate excitotoxicity in Huntington’s disease with proton magnetic spectroscopy.Lancet 343: 1170.

    PubMed  Article  CAS  Google Scholar 

  47. Trotti, D., Rossi, D., Gjesdal, O., Levy, L.M., Racagni, G., Danbolt, N.C. and Volterra, A. (1996) Peroxynitrite inhibits glutamate transporter subtypes.J. Biol. Chem. 271, 5976–5979.

    PubMed  Article  CAS  Google Scholar 

  48. Vige, X., Carreau, A., Scantton, B. and Nowicki, J.P. (1993) Antagonism by nitroarginine of glutamate-induced neurotoxicity in cultured neonatal rat cortical neurons. Prolonged application enhances neuroprotective efficacy.Neuroscience 55, 893–901.

    PubMed  Article  CAS  Google Scholar 

  49. Weber, G.F. (1999) Final common pathways in neurodegenerative diseases: regulatory role of the glutathione cycle.Neurosci Behav Reviews 23, 1079–1086.

    CAS  Google Scholar 

  50. Weill, C. L. and Greene, D. P. (1984) Prevention of natural motoneurone cell death by dibutyryl cyclic GMP.Nature 308: 452–455.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Carmina Montoliu or Marta Llansola or Pilar Monfort or Regina Corbalan or Iñigo Fernandez-Marticorena or Mari -Luz Hernandez-Viadel or Vicente Felipo.

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Montoliu, C., Llansola, M., Monfort, P. et al. Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death. neurotox res 3, 179–188 (2001). https://doi.org/10.1007/BF03033190

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Keywords

  • Cyclic GMP
  • glutamate
  • guanylate cyclase
  • neuroprotection
  • neurotoxicity
  • nitric oxide
  • NMDA receptors