Skip to main content
PMC home page
Molecular Medicine logoLink to Molecular Medicine
. 1997 Nov;3(11):750–764.

Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide.

M Leist 1, C Volbracht 1, S Kühnle 1, E Fava 1, E Ferrando-May 1, P Nicotera 1
PMCID: PMC2230245  PMID: 9407551

Abstract

BACKGROUND: Excitotoxicity and excess generation of nitric oxide (NO) are believed to be fundamental mechanisms in many acute and chronic neurodegenerative disorders. Disturbance of Ca2+ homeostasis and protein nitration/nitrosylation are key features in such conditions. Recently, a family of proteases collectively known as caspases has been implicated as common executor of a variety of death signals. In addition, overactivation of poly-(ADP-ribose) polymerase (PARP) has been observed in neuronal excitotoxicity. We therefore designed this study to investigate whether triggering of caspase activity and/or activation of PARP played a role in cerebellar granule cell (CGC) apoptosis elicited by peroxynitrite (ONOO-) or NO donors. MATERIALS AND METHODS: CGC from wild-type or PARP -/- mice were exposed to various nitric oxide donors. Caspase activation and its implications for membrane alterations, Ca2+ homeostasis, intracellular proteolysis, chromatin degradation, and cell death were investigated. RESULTS: CGC exposed to NO donors undergo apoptosis, which is mediated by excess synaptic release of excitotoxic mediators. This excitotoxic mechanism differs from direct NO toxicity in some other neuronal populations and does not involve PARP activation. Inhibition of caspases with different peptide substrates prevented cell death and the related features, including intracellular proteolysis, chromatin breakdown, and translocation of phosphatidylserine to the outer surface of the cell membrane. Increased Ca2+ influx following N-methyl-D-aspartate (NMDA) receptor (NMDA-R) activation was not inhibited by caspase inhibitors. CONCLUSIONS: In CGC, NO donors elicit apoptosis by a mechanism involving excitotoxic mediators, Ca2+ overload, and subsequent activation of caspases.

Full text

PDF
750

Images in this article

756Fig. 4
on p.756
757FIG. 5
on p.757
758FIG. 6
on p.758
759FIG. 7
on p.759

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ankarcrona M., Dypbukt J. M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton S. A., Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995 Oct;15(4):961–973. doi: 10.1016/0896-6273(95)90186-8. [DOI] [PubMed] [Google Scholar]
  2. Armstrong R. C., Aja T. J., Hoang K. D., Gaur S., Bai X., Alnemri E. S., Litwack G., Karanewsky D. S., Fritz L. C., Tomaselli K. J. Activation of the CED3/ICE-related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis. J Neurosci. 1997 Jan 15;17(2):553–562. doi: 10.1523/JNEUROSCI.17-02-00553.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beckman J. S., Chen J., Ischiropoulos H., Crow J. P. Oxidative chemistry of peroxynitrite. Methods Enzymol. 1994;233:229–240. doi: 10.1016/s0076-6879(94)33026-3. [DOI] [PubMed] [Google Scholar]
  4. Beckman J. S., Koppenol W. H. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996 Nov;271(5 Pt 1):C1424–C1437. doi: 10.1152/ajpcell.1996.271.5.C1424. [DOI] [PubMed] [Google Scholar]
  5. Beilharz E. J., Williams C. E., Dragunow M., Sirimanne E. S., Gluckman P. D. Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss. Brain Res Mol Brain Res. 1995 Mar;29(1):1–14. doi: 10.1016/0169-328x(94)00217-3. [DOI] [PubMed] [Google Scholar]
  6. Bonfoco E., Ceccatelli S., Manzo L., Nicotera P. Colchicine induces apoptosis in cerebellar granule cells. Exp Cell Res. 1995 May;218(1):189–200. doi: 10.1006/excr.1995.1147. [DOI] [PubMed] [Google Scholar]
  7. Bonfoco E., Leist M., Zhivotovsky B., Orrenius S., Lipton S. A., Nicotera P. Cytoskeletal breakdown and apoptosis elicited by NO donors in cerebellar granule cells require NMDA receptor activation. J Neurochem. 1996 Dec;67(6):2484–2493. doi: 10.1046/j.1471-4159.1996.67062484.x. [DOI] [PubMed] [Google Scholar]
  8. Charriaut-Marlangue C., Aggoun-Zouaoui D., Represa A., Ben-Ari Y. Apoptotic features of selective neuronal death in ischemia, epilepsy and gp 120 toxicity. Trends Neurosci. 1996 Mar;19(3):109–114. doi: 10.1016/s0166-2236(96)80039-7. [DOI] [PubMed] [Google Scholar]
  9. Charriaut-Marlangue C., Margaill I., Borrega F., Plotkine M., Ben-Ari Y. NG-nitro-L-arginine methyl ester reduces necrotic but not apoptotic cell death induced by reversible focal ischemia in rat. Eur J Pharmacol. 1996 Aug 29;310(2-3):137–140. doi: 10.1016/0014-2999(96)00385-8. [DOI] [PubMed] [Google Scholar]
  10. Charriaut-Marlangue C., Margaill I., Plotkine M., Ben-Ari Y. Early endonuclease activation following reversible focal ischemia in the rat brain. J Cereb Blood Flow Metab. 1995 May;15(3):385–388. doi: 10.1038/jcbfm.1995.48. [DOI] [PubMed] [Google Scholar]
  11. Choi D. W. Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci. 1995 Feb;18(2):58–60. [PubMed] [Google Scholar]
  12. Choi D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988 Oct;1(8):623–634. doi: 10.1016/0896-6273(88)90162-6. [DOI] [PubMed] [Google Scholar]
  13. Cryns V. L., Bergeron L., Zhu H., Li H., Yuan J. Specific cleavage of alpha-fodrin during Fas- and tumor necrosis factor-induced apoptosis is mediated by an interleukin-1beta-converting enzyme/Ced-3 protease distinct from the poly(ADP-ribose) polymerase protease. J Biol Chem. 1996 Dec 6;271(49):31277–31282. doi: 10.1074/jbc.271.49.31277. [DOI] [PubMed] [Google Scholar]
  14. Dimmeler S., Haendeler J., Nehls M., Zeiher A. M. Suppression of apoptosis by nitric oxide via inhibition of interleukin-1beta-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases. J Exp Med. 1997 Feb 17;185(4):601–607. doi: 10.1084/jem.185.4.601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dipasquale B., Marini A. M., Youle R. J. Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. Biochem Biophys Res Commun. 1991 Dec 31;181(3):1442–1448. doi: 10.1016/0006-291x(91)92101-o. [DOI] [PubMed] [Google Scholar]
  16. Do K. Q., Benz B., Grima G., Gutteck-Amsler U., Kluge I., Salt T. E. Nitric oxide precursor arginine and S-nitrosoglutathione in synaptic and glial function. Neurochem Int. 1996 Sep;29(3):213–224. doi: 10.1016/0197-0186(96)00002-2. [DOI] [PubMed] [Google Scholar]
  17. Friedlander R. M., Gagliardini V., Rotello R. J., Yuan J. Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta-converting enzyme-mediated apoptosis. J Exp Med. 1996 Aug 1;184(2):717–724. doi: 10.1084/jem.184.2.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Galpern W. R., Matthews R. T., Beal M. F., Isacson O. NGF attenuates 3-nitrotyrosine formation in a 3-NP model of Huntington's disease. Neuroreport. 1996 Nov 4;7(15-17):2639–2642. doi: 10.1097/00001756-199611040-00046. [DOI] [PubMed] [Google Scholar]
  19. Garthwaite G., Garthwaite J. Nitric oxide does not mediate acute glutamate neurotoxicity, nor is it neuroprotective, in rat brain slices. Neuropharmacology. 1994 Nov;33(11):1431–1438. doi: 10.1016/0028-3908(94)90046-9. [DOI] [PubMed] [Google Scholar]
  20. Garthwaite J., Boulton C. L. Nitric oxide signaling in the central nervous system. Annu Rev Physiol. 1995;57:683–706. doi: 10.1146/annurev.ph.57.030195.003343. [DOI] [PubMed] [Google Scholar]
  21. Gross S. S., Wolin M. S. Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol. 1995;57:737–769. doi: 10.1146/annurev.ph.57.030195.003513. [DOI] [PubMed] [Google Scholar]
  22. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  23. Gwag B. J., Lobner D., Koh J. Y., Wie M. B., Choi D. W. Blockade of glutamate receptors unmasks neuronal apoptosis after oxygen-glucose deprivation in vitro. Neuroscience. 1995 Oct;68(3):615–619. doi: 10.1016/0306-4522(95)00232-8. [DOI] [PubMed] [Google Scholar]
  24. Hampton M. B., Vanags D. M., Pörn-Ares M. I., Orrenius S. Involvement of extracellular calcium in phosphatidylserine exposure during apoptosis. FEBS Lett. 1996 Dec 16;399(3):277–282. doi: 10.1016/s0014-5793(96)01341-5. [DOI] [PubMed] [Google Scholar]
  25. Hara H., Friedlander R. M., Gagliardini V., Ayata C., Fink K., Huang Z., Shimizu-Sasamata M., Yuan J., Moskowitz M. A. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2007–2012. doi: 10.1073/pnas.94.5.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Henkart P. A. ICE family proteases: mediators of all apoptotic cell death? Immunity. 1996 Mar;4(3):195–201. doi: 10.1016/s1074-7613(00)80428-8. [DOI] [PubMed] [Google Scholar]
  27. Hewett S. J., Corbett J. A., McDaniel M. L., Choi D. W. Inhibition of nitric oxide formation does not protect murine cortical cell cultures from N-methyl-D-aspartate neurotoxicity. Brain Res. 1993 Oct 22;625(2):337–341. doi: 10.1016/0006-8993(93)91078-7. [DOI] [PubMed] [Google Scholar]
  28. Huang P. L., Fishman M. C. Genetic analysis of nitric oxide synthase isoforms: targeted mutation in mice. J Mol Med (Berl) 1996 Aug;74(8):415–421. doi: 10.1007/BF00217517. [DOI] [PubMed] [Google Scholar]
  29. Koh J. Y., Gwag B. J., Lobner D., Choi D. W. Potentiated necrosis of cultured cortical neurons by neurotrophins. Science. 1995 Apr 28;268(5210):573–575. doi: 10.1126/science.7725105. [DOI] [PubMed] [Google Scholar]
  30. Koopman G., Reutelingsperger C. P., Kuijten G. A., Keehnen R. M., Pals S. T., van Oers M. H. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994 Sep 1;84(5):1415–1420. [PubMed] [Google Scholar]
  31. Kruman I., Bruce-Keller A. J., Bredesen D., Waeg G., Mattson M. P. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci. 1997 Jul 1;17(13):5089–5100. doi: 10.1523/JNEUROSCI.17-13-05089.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kure S., Tominaga T., Yoshimoto T., Tada K., Narisawa K. Glutamate triggers internucleosomal DNA cleavage in neuronal cells. Biochem Biophys Res Commun. 1991 Aug 30;179(1):39–45. doi: 10.1016/0006-291x(91)91330-f. [DOI] [PubMed] [Google Scholar]
  33. Lei S. Z., Pan Z. H., Aggarwal S. K., Chen H. S., Hartman J., Sucher N. J., Lipton S. A. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron. 1992 Jun;8(6):1087–1099. doi: 10.1016/0896-6273(92)90130-6. [DOI] [PubMed] [Google Scholar]
  34. Leist M., Fava E., Montecucco C., Nicotera P. Peroxynitrite and nitric oxide donors induce neuronal apoptosis by eliciting autocrine excitotoxicity. Eur J Neurosci. 1997 Jul;9(7):1488–1498. doi: 10.1111/j.1460-9568.1997.tb01503.x. [DOI] [PubMed] [Google Scholar]
  35. Leist M., Nicotera P. Calcium and neuronal death. Rev Physiol Biochem Pharmacol. 1998;132:79–125. doi: 10.1007/BFb0004986. [DOI] [PubMed] [Google Scholar]
  36. Leist M., Single B., Castoldi A. F., Kühnle S., Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med. 1997 Apr 21;185(8):1481–1486. doi: 10.1084/jem.185.8.1481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Leist M., Single B., Künstle G., Volbracht C., Hentze H., Nicotera P. Apoptosis in the absence of poly-(ADP-ribose) polymerase. Biochem Biophys Res Commun. 1997 Apr 17;233(2):518–522. doi: 10.1006/bbrc.1997.6491. [DOI] [PubMed] [Google Scholar]
  38. Li Y., Chopp M., Jiang N., Yao F., Zaloga C. Temporal profile of in situ DNA fragmentation after transient middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1995 May;15(3):389–397. doi: 10.1038/jcbfm.1995.49. [DOI] [PubMed] [Google Scholar]
  39. Lipton S. A., Choi Y. B., Pan Z. H., Lei S. Z., Chen H. S., Sucher N. J., Loscalzo J., Singel D. J., Stamler J. S. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature. 1993 Aug 12;364(6438):626–632. doi: 10.1038/364626a0. [DOI] [PubMed] [Google Scholar]
  40. Loddick S. A., MacKenzie A., Rothwell N. J. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. Neuroreport. 1996 Jun 17;7(9):1465–1468. doi: 10.1097/00001756-199606170-00004. [DOI] [PubMed] [Google Scholar]
  41. Lynch T., Vasilakos J. P., Raser K., Keane K. M., Shivers B. D. Inhibition of the interleukin-1 beta converting enzyme family rescues neurons from apoptotic death. Mol Psychiatry. 1997 May;2(3):227–238. doi: 10.1038/sj.mp.4000242. [DOI] [PubMed] [Google Scholar]
  42. MacManus J. P., Rasquinha I., Black M. A., Laferriere N. B., Monette R., Walker T., Morley P. Glutamate-treated rat cortical neuronal cultures die in a way different from the classical apoptosis induced by staurosporine. Exp Cell Res. 1997 Jun 15;233(2):310–320. doi: 10.1006/excr.1997.3558. [DOI] [PubMed] [Google Scholar]
  43. Martin S. J., Finucane D. M., Amarante-Mendes G. P., O'Brien G. A., Green D. R. Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem. 1996 Nov 15;271(46):28753–28756. doi: 10.1074/jbc.271.46.28753. [DOI] [PubMed] [Google Scholar]
  44. Martin S. J., O'Brien G. A., Nishioka W. K., McGahon A. J., Mahboubi A., Saido T. C., Green D. R. Proteolysis of fodrin (non-erythroid spectrin) during apoptosis. J Biol Chem. 1995 Mar 24;270(12):6425–6428. doi: 10.1074/jbc.270.12.6425. [DOI] [PubMed] [Google Scholar]
  45. Meffert M. K., Calakos N. C., Scheller R. H., Schulman H. Nitric oxide modulates synaptic vesicle docking fusion reactions. Neuron. 1996 Jun;16(6):1229–1236. doi: 10.1016/s0896-6273(00)80149-x. [DOI] [PubMed] [Google Scholar]
  46. Meffert M. K., Premack B. A., Schulman H. Nitric oxide stimulates Ca(2+)-independent synaptic vesicle release. Neuron. 1994 Jun;12(6):1235–1244. doi: 10.1016/0896-6273(94)90440-5. [DOI] [PubMed] [Google Scholar]
  47. Meldrum B., Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990 Sep;11(9):379–387. doi: 10.1016/0165-6147(90)90184-a. [DOI] [PubMed] [Google Scholar]
  48. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  49. Nath R., Raser K. J., Stafford D., Hajimohammadreza I., Posner A., Allen H., Talanian R. V., Yuen P., Gilbertsen R. B., Wang K. K. Non-erythroid alpha-spectrin breakdown by calpain and interleukin 1 beta-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis. Biochem J. 1996 Nov 1;319(Pt 3):683–690. doi: 10.1042/bj3190683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Nicotera P., Leist M. Energy supply and the shape of death in neurons and lymphoid cells. Cell Death Differ. 1997 Aug;4(6):435–442. doi: 10.1038/sj.cdd.4400265. [DOI] [PubMed] [Google Scholar]
  51. Pang Z., Geddes J. W. Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid: acute excitotoxic necrosis and delayed apoptosis. J Neurosci. 1997 May 1;17(9):3064–3073. doi: 10.1523/JNEUROSCI.17-09-03064.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Portera-Cailliau C., Hedreen J. C., Price D. L., Koliatsos V. E. Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci. 1995 May;15(5 Pt 2):3775–3787. doi: 10.1523/JNEUROSCI.15-05-03775.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Regan R. F., Renn K. E., Panter S. S. NMDA neurotoxicity in murine cortical cell cultures is not attenuated by hemoglobin or inhibition of nitric oxide synthesis. Neurosci Lett. 1993 Apr 16;153(1):53–56. doi: 10.1016/0304-3940(93)90075-v. [DOI] [PubMed] [Google Scholar]
  54. Rink A., Fung K. M., Trojanowski J. Q., Lee V. M., Neugebauer E., McIntosh T. K. Evidence of apoptotic cell death after experimental traumatic brain injury in the rat. Am J Pathol. 1995 Dec;147(6):1575–1583. [PMC free article] [PubMed] [Google Scholar]
  55. Schulz J. B., Huang P. L., Matthews R. T., Passov D., Fishman M. C., Beal M. F. Striatal malonate lesions are attenuated in neuronal nitric oxide synthase knockout mice. J Neurochem. 1996 Jul;67(1):430–433. doi: 10.1046/j.1471-4159.1996.67010430.x. [DOI] [PubMed] [Google Scholar]
  56. Schulz J. B., Matthews R. T., Jenkins B. G., Ferrante R. J., Siwek D., Henshaw D. R., Cipolloni P. B., Mecocci P., Kowall N. W., Rosen B. R. Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neurosci. 1995 Dec;15(12):8419–8429. doi: 10.1523/JNEUROSCI.15-12-08419.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Schulz J. B., Weller M., Klockgether T. Potassium deprivation-induced apoptosis of cerebellar granule neurons: a sequential requirement for new mRNA and protein synthesis, ICE-like protease activity, and reactive oxygen species. J Neurosci. 1996 Aug 1;16(15):4696–4706. doi: 10.1523/JNEUROSCI.16-15-04696.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Siman R., Noszek J. C. Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron. 1988 Jun;1(4):279–287. doi: 10.1016/0896-6273(88)90076-1. [DOI] [PubMed] [Google Scholar]
  59. Snyder S. H. No NO prevents parkinsonism. Nat Med. 1996 Sep;2(9):965–966. doi: 10.1038/nm0996-965. [DOI] [PubMed] [Google Scholar]
  60. Stamler J. S., Jia L., Eu J. P., McMahon T. J., Demchenko I. T., Bonaventura J., Gernert K., Piantadosi C. A. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science. 1997 Jun 27;276(5321):2034–2037. doi: 10.1126/science.276.5321.2034. [DOI] [PubMed] [Google Scholar]
  61. Stamler J. S. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell. 1994 Sep 23;78(6):931–936. doi: 10.1016/0092-8674(94)90269-0. [DOI] [PubMed] [Google Scholar]
  62. Thornberry N. A. Interleukin-1 beta converting enzyme. Methods Enzymol. 1994;244:615–631. doi: 10.1016/0076-6879(94)44045-x. [DOI] [PubMed] [Google Scholar]
  63. Troy C. M., Stefanis L., Greene L. A., Shelanski M. L. Nedd2 is required for apoptosis after trophic factor withdrawal, but not superoxide dismutase (SOD1) downregulation, in sympathetic neurons and PC12 cells. J Neurosci. 1997 Mar 15;17(6):1911–1918. doi: 10.1523/JNEUROSCI.17-06-01911.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Troy C. M., Stefanis L., Prochiantz A., Greene L. A., Shelanski M. L. The contrasting roles of ICE family proteases and interleukin-1beta in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5635–5640. doi: 10.1073/pnas.93.11.5635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Wang Z. Q., Auer B., Stingl L., Berghammer H., Haidacher D., Schweiger M., Wagner E. F. Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev. 1995 Mar 1;9(5):509–520. doi: 10.1101/gad.9.5.509. [DOI] [PubMed] [Google Scholar]
  66. Yakovlev A. G., Knoblach S. M., Fan L., Fox G. B., Goodnight R., Faden A. I. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci. 1997 Oct 1;17(19):7415–7424. doi: 10.1523/JNEUROSCI.17-19-07415.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zhang J., Dawson V. L., Dawson T. M., Snyder S. H. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science. 1994 Feb 4;263(5147):687–689. doi: 10.1126/science.8080500. [DOI] [PubMed] [Google Scholar]
  68. Zhang J., Snyder S. H. Nitric oxide in the nervous system. Annu Rev Pharmacol Toxicol. 1995;35:213–233. doi: 10.1146/annurev.pa.35.040195.001241. [DOI] [PubMed] [Google Scholar]
  69. Zhivotovsky B., Burgess D. H., Vanags D. M., Orrenius S. Involvement of cellular proteolytic machinery in apoptosis. Biochem Biophys Res Commun. 1997 Jan 23;230(3):481–488. doi: 10.1006/bbrc.1996.6016. [DOI] [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES