Abstract
Nitric oxide (NO) is a free radical involved in the regulation of many cell functions and in the expression of several diseases. We have found that the antimalarial and antiinflammatory drug, chloroquine, is able to stimulate NO synthase (NOS) activity in murine, porcine, and human endothelial cells in vitro: the increase of enzyme activity is dependent on a de novo synthesis of some regulatory protein, as it is inhibited by cycloheximide but is not accompanied by an increased expression of inducible or constitutive NOS isoforms. Increased NO synthesis is, at least partly, responsible for chloroquine-induced inhibition of cell proliferation: indeed, NOS inhibitors revert the drug-evoked blockage of mitogenesis and ornithine decarboxylase activity in murine and porcine endothelial cells. The NOS-activating effect of chloroquine is dependent on its weak base properties, as it is exerted also by ammonium chloride, another lysosomotropic agent. Both compounds activate NOS by limiting the availability of iron: their stimulating effects on NO synthesis and inhibiting action on cell proliferation are reverted by iron supplementation with ferric nitrilotriacetate, and are mimicked by incubation with desferrioxamine. Our results suggest that NO synthesis can be stimulated in endothelial cells by chloroquine via an impairment of iron metabolism.
Full Text
The Full Text of this article is available as a PDF (317.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abiose A. K., Grossmann M., Tangphao O., Hoffman B. B., Blaschke T. F. Chloroquine-induced venodilation in human hand veins. Clin Pharmacol Ther. 1997 Jun;61(6):677–683. doi: 10.1016/S0009-9236(97)90103-X. [DOI] [PubMed] [Google Scholar]
- Anigbogu C. N., Adigun S. A., Inyang I., Adegunloye B. J. Chloroquine reduces blood pressure and forearm vascular resistance and increases forearm blood flow in healthy young adults. Clin Physiol. 1993 Mar;13(2):209–216. doi: 10.1111/j.1475-097x.1993.tb00381.x. [DOI] [PubMed] [Google Scholar]
- Armstrong N. J., Morgan E. H. The effect of lysosomotrophic bases and inhibitors of transglutaminase on iron uptake by immature erythroid cells. Biochim Biophys Acta. 1983 Apr 5;762(2):175–186. doi: 10.1016/0167-4889(83)90069-1. [DOI] [PubMed] [Google Scholar]
- Augustijns P., Geusens P., Verbeke N. Chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis. Eur J Clin Pharmacol. 1992;42(4):429–433. doi: 10.1007/BF00280130. [DOI] [PubMed] [Google Scholar]
- Ayajiki K., Kindermann M., Hecker M., Fleming I., Busse R. Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Circ Res. 1996 May;78(5):750–758. doi: 10.1161/01.res.78.5.750. [DOI] [PubMed] [Google Scholar]
- Bosia A., Ghigo D., Turrini F., Nissani E., Pescarmona G. P., Ginsburg H. Kinetic characterization of Na+/H+ antiport of Plasmodium falciparum membrane. J Cell Physiol. 1993 Mar;154(3):527–534. doi: 10.1002/jcp.1041540311. [DOI] [PubMed] [Google Scholar]
- Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9030–9033. doi: 10.1073/pnas.86.22.9030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Breuer W., Epsztejn S., Cabantchik Z. I. Iron acquired from transferrin by K562 cells is delivered into a cytoplasmic pool of chelatable iron(II). J Biol Chem. 1995 Oct 13;270(41):24209–24215. doi: 10.1074/jbc.270.41.24209. [DOI] [PubMed] [Google Scholar]
- Byrd T. F., Horwitz M. A. Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest. 1991 Jul;88(1):351–357. doi: 10.1172/JCI115301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chandra S., Adhikary G., Sikdar R., Sen P. C. The in vivo inhibition of transport enzyme activities by chloroquine in different organs of rat is reversible. Mol Cell Biochem. 1992 Dec 2;118(1):15–21. doi: 10.1007/BF00249690. [DOI] [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Clark I. A., Rockett K. A., Cowden W. B. Possible central role of nitric oxide in conditions clinically similar to cerebral malaria. Lancet. 1992 Oct 10;340(8824):894–896. doi: 10.1016/0140-6736(92)93295-x. [DOI] [PubMed] [Google Scholar]
- Clark I. A., Rockett K. A., Cowden W. B. Proposed link between cytokines, nitric oxide and human cerebral malaria. Parasitol Today. 1991 Aug;7(8):205–207. doi: 10.1016/0169-4758(91)90142-b. [DOI] [PubMed] [Google Scholar]
- Edwards G., Looareesuwan S., Davies A. J., Wattanagoon Y., Phillips R. E., Warrell D. A. Pharmacokinetics of chloroquine in Thais: plasma and red-cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria. Br J Clin Pharmacol. 1988 Apr;25(4):477–485. doi: 10.1111/j.1365-2125.1988.tb03332.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Espinosa-Aguirre J. J., Ramírez Santos J., Cortinas de Nava C. Influence of the Uvr repair system on the mutagenicity of antiparasitic drugs. Mutat Res. 1989 Mar;222(3):161–166. doi: 10.1016/0165-1218(89)90132-8. [DOI] [PubMed] [Google Scholar]
- Ghigo D., Brizzi M. F., Avanzi G. C., Bussolino F., Garbarino G., Costamagna C., Pegoraro L., Bosia A. Evidence for a role of the Na+/H+ exchanger in the colony-stimulating-factor-induced ornithine decarboxylase activity and proliferation of the human cell line M-07e. J Cell Physiol. 1990 Oct;145(1):147–154. doi: 10.1002/jcp.1041450120. [DOI] [PubMed] [Google Scholar]
- Ghigo D., Todde R., Ginsburg H., Costamagna C., Gautret P., Bussolino F., Ulliers D., Giribaldi G., Deharo E., Gabrielli G. Erythrocyte stages of Plasmodium falciparum exhibit a high nitric oxide synthase (NOS) activity and release an NOS-inducing soluble factor. J Exp Med. 1995 Sep 1;182(3):677–688. doi: 10.1084/jem.182.3.677. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goenka M. K., Kochhar R., Tandia B., Mehta S. K. Chloroquine for mild to moderately active ulcerative colitis: comparison with sulfasalazine. Am J Gastroenterol. 1996 May;91(5):917–921. [PubMed] [Google Scholar]
- Gross S. S., Jaffe E. A., Levi R., Kilbourn R. G. Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages. Biochem Biophys Res Commun. 1991 Aug 15;178(3):823–829. doi: 10.1016/0006-291x(91)90965-a. [DOI] [PubMed] [Google Scholar]
- 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]
- Gryglewski R. J., Moncada S., Palmer R. M. Bioassay of prostacyclin and endothelium-derived relaxing factor (EDRF) from porcine aortic endothelial cells. Br J Pharmacol. 1986 Apr;87(4):685–694. doi: 10.1111/j.1476-5381.1986.tb14586.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iacopetta B. J., Morgan E. H. The kinetics of transferrin endocytosis and iron uptake from transferrin in rabbit reticulocytes. J Biol Chem. 1983 Aug 10;258(15):9108–9115. [PubMed] [Google Scholar]
- Jancinová V., Nosál R., Petríková M. On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb Res. 1994 Jun 1;74(5):495–504. doi: 10.1016/0049-3848(94)90270-4. [DOI] [PubMed] [Google Scholar]
- Kao J. P., Harootunian A. T., Tsien R. Y. Photochemically generated cytosolic calcium pulses and their detection by fluo-3. J Biol Chem. 1989 May 15;264(14):8179–8184. [PubMed] [Google Scholar]
- Karin M., Mintz B. Receptor-mediated endocytosis of transferrin in developmentally totipotent mouse teratocarcinoma stem cells. J Biol Chem. 1981 Apr 10;256(7):3245–3252. [PubMed] [Google Scholar]
- Knowles R. G., Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994 Mar 1;298(Pt 2):249–258. doi: 10.1042/bj2980249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knowles R. G., Palacios M., Palmer R. M., Moncada S. Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5159–5162. doi: 10.1073/pnas.86.13.5159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kremsner P. G., Neifer S., Rasenack T., Bienzle U. Interference by antimalarial drugs with the in-vitro production of reactive nitrogen intermediates by murine macrophages. J Antimicrob Chemother. 1993 Mar;31(3):385–392. doi: 10.1093/jac/31.3.385. [DOI] [PubMed] [Google Scholar]
- Krogstad D. J., Schlesinger P. H. Acid-vesicle function, intracellular pathogens, and the action of chloroquine against Plasmodium falciparum. N Engl J Med. 1987 Aug 27;317(9):542–549. doi: 10.1056/NEJM198708273170905. [DOI] [PubMed] [Google Scholar]
- Kueng W., Silber E., Eppenberger U. Quantification of cells cultured on 96-well plates. Anal Biochem. 1989 Oct;182(1):16–19. doi: 10.1016/0003-2697(89)90710-0. [DOI] [PubMed] [Google Scholar]
- Landewé R. B., Miltenburg A. M., Verdonk M. J., Verweij C. L., Breedveld F. C., Daha M. R., Dijkmans B. A. Chloroquine inhibits T cell proliferation by interfering with IL-2 production and responsiveness. Clin Exp Immunol. 1995 Oct;102(1):144–151. doi: 10.1111/j.1365-2249.1995.tb06648.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lejeune P., Lagadec P., Onier N., Pinard D., Ohshima H., Jeannin J. F. Nitric oxide involvement in tumor-induced immunosuppression. J Immunol. 1994 May 15;152(10):5077–5083. [PubMed] [Google Scholar]
- Lepoivre M., Fieschi F., Coves J., Thelander L., Fontecave M. Inactivation of ribonucleotide reductase by nitric oxide. Biochem Biophys Res Commun. 1991 Aug 30;179(1):442–448. doi: 10.1016/0006-291x(91)91390-x. [DOI] [PubMed] [Google Scholar]
- Mackenzie A. H. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med. 1983 Jul 18;75(1A):40–45. doi: 10.1016/0002-9343(83)91269-x. [DOI] [PubMed] [Google Scholar]
- McCall T., Vallance P. Nitric oxide takes centre-stage with newly defined roles. Trends Pharmacol Sci. 1992 Jan;13(1):1–6. doi: 10.1016/0165-6147(92)90002-n. [DOI] [PubMed] [Google Scholar]
- Mellouk S., Green S. J., Nacy C. A., Hoffman S. L. IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism. J Immunol. 1991 Jun 1;146(11):3971–3976. [PubMed] [Google Scholar]
- Mellouk S., Hoffman S. L., Liu Z. Z., de la Vega P., Billiar T. R., Nussler A. K. Nitric oxide-mediated antiplasmodial activity in human and murine hepatocytes induced by gamma interferon and the parasite itself: enhancement by exogenous tetrahydrobiopterin. Infect Immun. 1994 Sep;62(9):4043–4046. doi: 10.1128/iai.62.9.4043-4046.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michel T., Feron O. Nitric oxide synthases: which, where, how, and why? J Clin Invest. 1997 Nov 1;100(9):2146–2152. doi: 10.1172/JCI119750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michel T., Li G. K., Busconi L. Phosphorylation and subcellular translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6252–6256. doi: 10.1073/pnas.90.13.6252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Molina y Vedia L., McDonald B., Reep B., Brüne B., Di Silvio M., Billiar T. R., Lapetina E. G. Nitric oxide-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP-ribosylation. J Biol Chem. 1992 Dec 15;267(35):24929–24932. [PubMed] [Google Scholar]
- Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
- Nathan C., Xie Q. W. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994 Sep 23;78(6):915–918. doi: 10.1016/0092-8674(94)90266-6. [DOI] [PubMed] [Google Scholar]
- Newman S. L., Gootee L., Brunner G., Deepe G. S., Jr Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis. J Clin Invest. 1994 Apr;93(4):1422–1429. doi: 10.1172/JCI117119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nussler A. K., Rénia L., Pasquetto V., Miltgen F., Matile H., Mazier D. In vivo induction of the nitric oxide pathway in hepatocytes after injection with irradiated malaria sporozoites, malaria blood parasites or adjuvants. Eur J Immunol. 1993 Apr;23(4):882–887. doi: 10.1002/eji.1830230417. [DOI] [PubMed] [Google Scholar]
- Nüssler A., Drapier J. C., Rénia L., Pied S., Miltgen F., Gentilini M., Mazier D. L-arginine-dependent destruction of intrahepatic malaria parasites in response to tumor necrosis factor and/or interleukin 6 stimulation. Eur J Immunol. 1991 Jan;21(1):227–230. doi: 10.1002/eji.1830210134. [DOI] [PubMed] [Google Scholar]
- Octave J. N., Schneider Y. J., Hoffmann P., Trouet A., Crichton R. R. Transferrin protein and iron uptake by cultured rat fibroblasts. FEBS Lett. 1979 Dec 1;108(1):127–130. doi: 10.1016/0014-5793(79)81193-x. [DOI] [PubMed] [Google Scholar]
- Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
- Palmer R. M., Moncada S. A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jan 16;158(1):348–352. doi: 10.1016/s0006-291x(89)80219-0. [DOI] [PubMed] [Google Scholar]
- Pegg A. E. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988 Feb 15;48(4):759–774. [PubMed] [Google Scholar]
- Pegg A. E. Recent advances in the biochemistry of polyamines in eukaryotes. Biochem J. 1986 Mar 1;234(2):249–262. doi: 10.1042/bj2340249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Phillips R. E., Warrell D. A., Edwards G., Galagedera Y., Theakston R. D., Abeysekera D. T., Dissanayaka P. Divided dose intramuscular regimen and single dose subcutaneous regimen for chloroquine: plasma concentrations and toxicity in patients with malaria. Br Med J (Clin Res Ed) 1986 Jul 5;293(6538):13–16. doi: 10.1136/bmj.293.6538.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Picot S., Peyron F., Donadille A., Vuillez J. P., Barbe G., Ambroise-Thomas P. Chloroquine-induced inhibition of the production of TNF, but not of IL-6, is affected by disruption of iron metabolism. Immunology. 1993 Sep;80(1):127–133. [PMC free article] [PubMed] [Google Scholar]
- Rabie A., Simpson R. J., Bomford A., Cunninghame-Graham D., Peters T. J. Relationship between duodenal cytosolic aconitase activity and iron status in the mouse. Biochim Biophys Acta. 1995 Dec 14;1245(3):414–420. doi: 10.1016/0304-4165(95)00120-4. [DOI] [PubMed] [Google Scholar]
- Rockett K. A., Awburn M. M., Aggarwal B. B., Cowden W. B., Clark I. A. In vivo induction of nitrite and nitrate by tumor necrosis factor, lymphotoxin, and interleukin-1: possible roles in malaria. Infect Immun. 1992 Sep;60(9):3725–3730. doi: 10.1128/iai.60.9.3725-3730.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rockett K. A., Awburn M. M., Cowden W. B., Clark I. A. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun. 1991 Sep;59(9):3280–3283. doi: 10.1128/iai.59.9.3280-3283.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rothe M. J., Kerdel F. A. Treatment of cutaneous lupus erythematosus. Lupus. 1992 Dec;1(6):351–356. doi: 10.1177/096120339200100603. [DOI] [PubMed] [Google Scholar]
- Rouault T. A., Klausner R. D. Iron-sulfur clusters as biosensors of oxidants and iron. Trends Biochem Sci. 1996 May;21(5):174–177. [PubMed] [Google Scholar]
- Sayers M. E., Mazanec D. J. Use of antimalarial drugs for the treatment of psoriatic arthritis. Am J Med. 1992 Oct;93(4):474–475. doi: 10.1016/0002-9343(92)90183-c. [DOI] [PubMed] [Google Scholar]
- Schmidt H. H., Walter U. NO at work. Cell. 1994 Sep 23;78(6):919–925. doi: 10.1016/0092-8674(94)90267-4. [DOI] [PubMed] [Google Scholar]
- Schwarzer E., Turrini F., Arese P. A luminescence method for the quantitative determination of phagocytosis of erythrocytes, of malaria-parasitized erythrocytes and of malarial pigment. Br J Haematol. 1994 Dec;88(4):740–745. doi: 10.1111/j.1365-2141.1994.tb05112.x. [DOI] [PubMed] [Google Scholar]
- Seguin M. C., Klotz F. W., Schneider I., Weir J. P., Goodbary M., Slayter M., Raney J. J., Aniagolu J. U., Green S. J. Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells. J Exp Med. 1994 Jul 1;180(1):353–358. doi: 10.1084/jem.180.1.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Slater A. F., Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature. 1992 Jan 9;355(6356):167–169. doi: 10.1038/355167a0. [DOI] [PubMed] [Google Scholar]
- Stamler J. S., Simon D. I., Osborne J. A., Mullins M. E., Jaraki O., Michel T., Singel D. J., Loscalzo J. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):444–448. doi: 10.1073/pnas.89.1.444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taylor-Robinson A. W., Phillips R. S., Severn A., Moncada S., Liew F. Y. The role of TH1 and TH2 cells in a rodent malaria infection. Science. 1993 Jun 25;260(5116):1931–1934. doi: 10.1126/science.8100366. [DOI] [PubMed] [Google Scholar]
- Tegnér R., Tomé F. M., Godeau P., Lhermitte F., Fardeau M. Morphological study of peripheral nerve changes induced by chloroquine treatment. Acta Neuropathol. 1988;75(3):253–260. doi: 10.1007/BF00690533. [DOI] [PubMed] [Google Scholar]
- Thomas J. A., Buchsbaum R. N., Zimniak A., Racker E. Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ. Biochemistry. 1979 May 29;18(11):2210–2218. doi: 10.1021/bi00578a012. [DOI] [PubMed] [Google Scholar]
- Valls V., Ena J., Enríquez-De-Salamanca R. Low-dose oral chloroquine in patients with porphyria cutanea tarda and low-moderate iron overload. J Dermatol Sci. 1994 Jun;7(3):169–175. doi: 10.1016/0923-1811(94)90092-2. [DOI] [PubMed] [Google Scholar]
- Weiss G., Werner-Felmayer G., Werner E. R., Grünewald K., Wachter H., Hentze M. W. Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med. 1994 Sep 1;180(3):969–976. doi: 10.1084/jem.180.3.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wellems T. E. Malaria. How chloroquine works. Nature. 1992 Jan 9;355(6356):108–109. doi: 10.1038/355108a0. [DOI] [PubMed] [Google Scholar]
- White N. J., Miller K. D., Churchill F. C., Berry C., Brown J., Williams S. B., Greenwood B. M. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations. N Engl J Med. 1988 Dec 8;319(23):1493–1500. doi: 10.1056/NEJM198812083192301. [DOI] [PubMed] [Google Scholar]
- Williams R. L., Courtneidge S. A., Wagner E. F. Embryonic lethalities and endothelial tumors in chimeric mice expressing polyoma virus middle T oncogene. Cell. 1988 Jan 15;52(1):121–131. doi: 10.1016/0092-8674(88)90536-3. [DOI] [PubMed] [Google Scholar]
- Wink D. A., Kasprzak K. S., Maragos C. M., Elespuru R. K., Misra M., Dunams T. M., Cebula T. A., Koch W. H., Andrews A. W., Allen J. S. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991 Nov 15;254(5034):1001–1003. doi: 10.1126/science.1948068. [DOI] [PubMed] [Google Scholar]
- 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]