The Role of Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activation in Focal Cerebral Ischemia



Poly(ADP-ribosyl)ation is the post-translational modification of proteins operated by poly(ADP-ribose) polymerases (PARPs). PARPs are enzymes that are able to catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD) to target proteins and are particularly abundant in cell nuclei, where they play a key role in the maintenance of homeostasis. Poly(ADP-ribosyl)ation significantly affects protein functioning because of the high negative charge and steric hindrance conferred by the chains of poly(ADP-ribose) (PAR). PARP-1 is the founding member and the most commonly studied of these enzymes and shows the highest poly(ADP-ribosyl)ating activity. Sequences encoding novel PARPs have been identified and, overall, the PARP superfamily is a growing family of enzymes with numerous members with roles that are yet to be identified (Ame et al. 2004; Smith 2001).


Focal Cerebral Ischemia Apoptosis Induce Factor Nicotinamide Adenine Dinucleotide Ischemic Brain Injury Bilateral Common Carotid Artery Occlusion 


  1. Abdelkarim GE, Gertz K, Harms C, Katchanov J, Dirnagl U, Szabo C, Endres M (2001) Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med 7:255–260PubMedGoogle Scholar
  2. Agarwal ML, Agarwal A, Taylor WR, Wang ZQ, Wagner EF, Stark GR (1997) Defective induction and normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase. Oncogene 15:1035–1041PubMedGoogle Scholar
  3. Akiyama T, Takasawa S, Nata K, Kobayashi S, Abe M, Shervani NJ, Ikeda T, Nakagawa K, Unno M, Matsuno S, Okamoto H (2001) Activation of Reg gene, a gene for insulin-producing β-cell regeneration: Poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proc Natl Acad Sci 98:48–53PubMedGoogle Scholar
  4. Alano CC, Ying W, Swanson RA (2004) Poly(ADP-ribose) polymerase-1-mediated cell death in astrocytes requires NAD+ depletion and mitochondrial permeability transition. J Biol Chem 279:18895–18902PubMedGoogle Scholar
  5. Althaus FR, Naegeli H, Realini C, Mathis G, Loetscher P, Mattenberger M (1990) The poly-ADP-ribosylation system of higher eukaryotes: a protein shuttle mechanism in chromatin? Acta Biol Hung 41:9–18PubMedGoogle Scholar
  6. Altznauer F, Conus S, Cavalli A, Folkers G, Simon HU (2004) Calpain-1 regulates Bax and subsequent Smac-dependent caspase-3 activation in neutrophil apoptosis. J Biol Chem 279:5947–5957PubMedGoogle Scholar
  7. Ame JC, Spenlehauer C, de Murcia G (2004) The PARP superfamily. Bioessays 26:882–893PubMedGoogle Scholar
  8. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD, Poirier GG, Dawson VL, Dawson TM (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A 103:18308–18313PubMedGoogle Scholar
  9. Beal MF (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23:298–304PubMedGoogle Scholar
  10. Berger NA (1985) Poly (ADP-ribose) in the cellular response to DNA damage. Radiat Res 101:4–15PubMedGoogle Scholar
  11. Butler AJ, Ordahl CP (1999) Poly(ADP-ribose)polymerase binds with transcription enhancer factor 1 to MCAT1 elements to regulate muscle-specific transcription. Mol Cell Biol 19:296–306PubMedGoogle Scholar
  12. Cao G, Clark RS, Pei W, Yin W, Zhang F, Sun FY, Graham SH, Chen J (2003) Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab 23:1137–1150PubMedGoogle Scholar
  13. Carty SM, Greenleaf AL (2002) Hyperphosphorylated C-terminal repeat domain-associating proteins in the nuclear proteome link transcription to DNA/chromatin modification and RNA processing. Mol Cell Proteomics 1:598–610PubMedGoogle Scholar
  14. Chang P, Jacobson MK, Mitchinson TJ (2004) Poly(ADP-ribose is required for spindle assembly and structure. Nature 432:645–649PubMedGoogle Scholar
  15. Chiarugi A (2002a) Inhibitors of poly(ADP-ribose) polymerase-1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats. Br J Pharmacol 137:761–770PubMedGoogle Scholar
  16. Chiarugi A (2002b) PARP-1: killer or conspirator? The suicide hypothesis revisited. Trends Pharmacol Sci 23:122–129PubMedGoogle Scholar
  17. Chiarugi A, Meli E, Calvani M, Picca R, Baronti R, Camaioni E, Costantino G, Marinozzi M, Pellegrini-Giampietro DE, Pellicciari R, Moroni F (2003) Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-1: pharmacological characterization and neuroprotective effects in an in vitro model of cerebral ischemia. J Pharmacol Exp Ther 305:943–949PubMedGoogle Scholar
  18. Chiarugi A, Moskowitz MA (2003) Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem 85:306–317PubMedGoogle Scholar
  19. Cosi C, Suzuki H, Milani D, Facci L, Menegazzi M, Vantini G, Kanai Y, Skaper SD (1994) Poly(ADP-ribose) polymerase: early involvement in glutamate-induced neurotoxicity in cultured cerebellar granule cells. J Neurosci Res 39:38–46PubMedGoogle Scholar
  20. Costantino G, Macchiarulo A, Camaioni E, Pellicciari R (2001) Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J Med Chem 44:3794Google Scholar
  21. Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellechia M, Blomgren K, Plesnila N (2005) Apoptosis-inducing factor triggered by poly(ADP-Ribose) polymerase and bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 25:10262–10272PubMedGoogle Scholar
  22. D’Amours D, Desnoyers S, Poirier GG (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342:249–268PubMedGoogle Scholar
  23. de Murcia G, Huletsky A, Lamarre D, Gaudreau A, Poujet J, Daune M, Poirier GG (1986) Modulation of chromatin superstructure induced by poly(ADP-ribose) synthesis and degradation. Proc Natl Acad Sci 261:7011–7017Google Scholar
  24. de Murcia G, Huletsky A, Poirier GG (1988) Modulation of chromatin structure by poly(ADP-ribosyl)ation. Biochem Cell Biol 66:626–635PubMedGoogle Scholar
  25. Ditsworth D, Zong WX, Thompson CB (2007) Activation of poly(ADP)-ribose polymerase (PARP-1) induces release of the pro-inflammatory mediator HMGB1 from the nucleus. J Biol Chem 282:17845–17854PubMedGoogle Scholar
  26. Dumitriu IE, Voll RE, Kolowos W, Gaipl US, Heyder P, Kalden JR, Herrmann M (2004) UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase. Cell Death Differ 11:314–320PubMedGoogle Scholar
  27. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095PubMedGoogle Scholar
  28. Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab 17:1143–1151PubMedGoogle Scholar
  29. Faraco G, Fossati S, Bianchi ME, Patrone M, Pedrazzi M, Sparatore B, Moroni F, Chiarugi A (2007) High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem 103:590–603PubMedGoogle Scholar
  30. Ferraris D, Ficco RP, Dain D, Ginski M, Lautar S, Lee-Wisdom K, Liang S, Lin Q, Lu MX, Morgan L, Thomas B, Williams LR, Zhang J, Zhou Y, Kalish VJ (2003a) Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. Bioorg Med Chem 11:3695–3707PubMedGoogle Scholar
  31. Ferraris D, Ficco RP, Pahutski T, Lautar S, Huang S, Zhang J, Kalish V (2003b) Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 3: In vitro evaluation of 1, 3, 4, 5-tetrahydro-benzo[c][1, 6]- and [c][1, 7]-naphthyridin-6-ones. Bioorg Med Chem Lett 13:2513–2518PubMedGoogle Scholar
  32. Ferraris D, Ko YS, Pahutski T, Ficco RP, Serdyuk L, Alemu C, Bradford C, Chiou T, Hoover R, Huang S, Lautar S, Liang S, Lin Q, Lu MX, Mooney M, Morgan L, Qian Y, Tran S, Williams LR, Wu QY, Zhang J, Zou Y, Kalish V (2003c) Design and synthesis of poly ADP-ribose polymerase-1 inhibitors. 2. Biological evaluation of aza-5[H]-phenanthridin-6-ones as potent, aqueous-soluble compounds for the treatment of ischemic injuries. J Med Chem 46:3138–3151PubMedGoogle Scholar
  33. Feuerstain GZ, Wang X, Barone FC (1998) The role of cytokine in the pathology of stroke and neurotrauma. Neuroimmunomodul 5:143–159Google Scholar
  34. Gan L, Anton KE, Masterson BA, Vincent VA, Ye S, Gonzalez-Zulueta M (2002) Specific interference with gene expression and gene function mediated by long dsRNA in neural cells. J Neurosci Methods 121:151–157PubMedGoogle Scholar
  35. Gao G, Dou QP (2000) N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death. J Cell Biochem 80:53–72PubMedGoogle Scholar
  36. Goto S, Xue R, Sugo N, Sawada M, Blizzard KK, Poitras MF, Johns DC, Dawson TM, Dawson VL, Crain BJ, Traistman RG, Mori S, Hurn PD (2002) Poly(ADP-ribose) polymerase impairs early and long-term experimental stroke recovery. Stroke 33:1101–1106PubMedGoogle Scholar
  37. Ha HC, Hester LD, Snyder SH (2002) Poly(ADP-ribose) polymerase-1 dependence of stress-induced transcription factors and associated gene expression in glia. Proc Natl Acad Sci 99:3270–3275PubMedGoogle Scholar
  38. Ha HC, Snyder SH (2000) Poly (ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis 7:225–239PubMedGoogle Scholar
  39. Haddad M, Rhinn H, Bloquel C, Coqueran B, Szabo C, Plotkine M, Scherman D, Margaill I (2006) Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice. Br J Pharmacol 149:23–30PubMedGoogle Scholar
  40. Hassa PO, Covic M, Hasan S, Imhof R, Hottinger MO (2001) The enzymatic and DNA binding activity of PARP-1 are not required for NF-kappaB coactivator function. J Biol Chem 276:45588–45597PubMedGoogle Scholar
  41. Hassa PO, Hottinger MO (1999) A role of poly(ADP-ribose) polymerase in NF-kB transcriptional activation. Biol Chem 380:953–959PubMedGoogle Scholar
  42. Herceg Z, Wang ZQ (2001) Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477:97–110PubMedGoogle Scholar
  43. Homburg S, Visochek L, Moran N, Dantzer F, Priel E, Asculai E, Schwartz D, Rotter V, Dekel N, Cohen-Armon M (2000) A fast signal induced activation of poly(ADP-ribose)polymerase: a downstream target of phospholipase C. J Cell Biol 150:293–307PubMedGoogle Scholar
  44. Hong SJ, Dawson TM, Dawson VL (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci 25:259–264PubMedGoogle Scholar
  45. Iwashita A, Tojo N, Matsuura S, Yamazaki S, Kamijo K, Ishida J, Yamamoto H, Hattori K, Matsuoka N, Mutoh S (2004) A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3, 6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazo linone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia. J Pharmacol Exp Ther 310:425–436PubMedGoogle Scholar
  46. Kim JB, Sig CJ, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–6421PubMedGoogle Scholar
  47. Koedel U, Pfister HW (1999) Oxidative stress in bacterial meningitis. Brain Pathol 9:57–67PubMedGoogle Scholar
  48. Kofler J, Otsuka T, Zhang Z, Noppens R, Grafe MR, Koh DW, Dawson VL, de Murcia JM, Hurn PD, Traystman RJ (2006) Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia. J Cereb Blood Flow Metab 26:135–141PubMedGoogle Scholar
  49. Koh SH, Park Y, Song CW, Kim JG, Kim K, Kim J, Kim MH, Lee SR, Kim DW, Yu HJ, Chang DI, Hwang SJ, Kim SH (2004) The effect of PARP inhibitor on ischaemic cell death, its related inflammation and survival signals. Eur J Neurosci 20:1461–1472PubMedGoogle Scholar
  50. Komjati K, Mabley JG, Virag L, Southan GJ, Salzman AL, Szabo C (2004) Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. Int J Mol Med 13:373–382PubMedGoogle Scholar
  51. Kraus WL, Lis JT (2003) PARP goes transcription. Cell 113:677–683PubMedGoogle Scholar
  52. Kun E, Kirsten E, Ordahl CP (2002) Coenzymatic activity of randomly broken or intact double-stranded DNAs in auto and histone H1 trans-poly(ADP-ribosylation), catalyzed by poly(ADP-ribose) polymerase (PARP I). J Biol Chem 277:39066–39069PubMedGoogle Scholar
  53. Le Page C, Sanceau J, Drapier JC, Wietzerbin J (1998) Inhibitors of ADP-ribosylation impair inducible nitric oxide synthase gene transcription through inhibition of NF-kB activation. Biochem Biophys Res Comm 243:451–457PubMedGoogle Scholar
  54. Lee JM, Grabb MC, Zipfel GJ, Choi DW (2000) Brain tissue responses to ischemia. J Clin Invest 106:723–731PubMedGoogle Scholar
  55. Lenzser G, Kis B, Snipes JA, Gaspar T, Sandor P, Komjati K, Szabo C, Busija DW (2007) Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats. J Cereb Blood Flow Metab 27:1318–1326PubMedGoogle Scholar
  56. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568PubMedGoogle Scholar
  57. Liu J, Ying W, Massa S, Duriez PJ, Swanson RA, Poirier GG, Sharp FR (2000) Effects of transient global ischemia and kainate on poly(ADP-ribose) polymerase (PARP) gene expression and proteolytic cleavage in gerbil and rat brains. Brain Res Mol Brain Res 80:7–16PubMedGoogle Scholar
  58. Lo EH, Bosque-Hamilton P, Meng W (1998) Inhibition of poly(ADP-ribose) polymerase: reduction of ischemic injury and attenuation of N-methyl-D-aspartate-induced neurotransmitter dysregulation. Stroke 29:830–836PubMedGoogle Scholar
  59. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415PubMedGoogle Scholar
  60. Love S, Barber R, Wilcock GK (2000) Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 26:55–66PubMedGoogle Scholar
  61. Mandir AS, Poitras MF, Berliner AR, Herring WJ, Guastella DB, Feldman A, Poirier GG, Wang ZQ, Dawson TM, Dawson VL (2000) NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci 20:8005–8011PubMedGoogle Scholar
  62. Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL, Dawson TM (1999) Poly(ADP-ribose)polymerase activation mediates 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced parkynsonism. Proc Natl Acad Sci 96:5774–5779PubMedGoogle Scholar
  63. Mattson MP, Camandola S (2001) NF-kB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107:247–254PubMedGoogle Scholar
  64. Mattson MP, Culmsee C, Yu Z, Camandola S (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 74:443–456PubMedGoogle Scholar
  65. Moroni F, Meli E, Peruginelli F, Chiarugi A, Cozzi A, Picca R, Romagnoli P, Pellicciari R, Pellegrini-Giampietro DE (2001) Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. Cell Death Diff 8:921–932Google Scholar
  66. Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, Susin SA (2007) Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol 27:4844–4862PubMedGoogle Scholar
  67. Nagayama T, Simon RP, Chen D, Henshall DC, Pei W, Stetler RA, Chen J (2000) Activation of poly(ADP-ribose) polymerase in the rat hippocampus may contribute to cellular recovery following sublethal transient global ischemia. J Neurochem 74:1636–1645PubMedGoogle Scholar
  68. Nakajima H, Kakui N, Ohkuma K, Ishikawa M, Hasegawa T (2004a) A newly synthesized poly(ADP-ribose) polymerase inhibitor, 2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one (DR2313): pharmacological profiles, neuroprotective effects, and therapeutic time window in cerebral ischemia in rats. J Pharmacol Exp Ther 312:472–481PubMedGoogle Scholar
  69. Nakajima H, Nagaso H, Kakui N, Ishikawa M, Hiranuma T, Hoshiko S (2004b) Critical role of the automodification of poly(ADP-ribose) polymerase-1 in nuclear factor-kappaB-dependent gene expression in primary cultured mouse glial cells. J Biol Chem 279:42774–42786PubMedGoogle Scholar
  70. Nirodi C, NagDas S, Gygi SP, Olson G, Ruedi A, Richmond A (2001) A role for poly(ADP-ribose) polymerase (PARP) in the transcriptional regulation of the melanoma growth stimulatory activity (CXCL1) gene expression. J Biol Chem 276:9366–9374PubMedGoogle Scholar
  71. Oliver FJ, Menissier-de Murcia J, Nacci C, Decker P, Andriantsitohania R, Muller S, de la Rubia G, Stoclet JC, de Murcia G (1999) Resistance to endotoxic shock as a consequence of defective NF-kB activation in poly(ADP-ribose) polymerase-1 deficient mice. EMBO J 18:4446–4454PubMedGoogle Scholar
  72. Paschen W, Olah L, Mies G (2000) Effect of transient focal ischemia of mouse brain on energy state and NAD levels: no evidence that NAD depletion plays a major role in secondary disturbances of energy metabolism. J Neurochem 75:1675–1680PubMedGoogle Scholar
  73. Plaschke K, Kopitz J, Weigand MA, Martin E, Bardenheuer HJ (2000) The neuroprotective effect of cerebral poly (ADP-ribose) polymerase inhibition in a rat model of global ischemia. Neurosci Lett 284:109–112PubMedGoogle Scholar
  74. Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466PubMedGoogle Scholar
  75. Poirier GG, de Murcia G, Jongstra-Bilen J, Mandel P (1982) Poly(ADP-ribosyl)ation of polynucleosomes causes relaxation of chromatin structure. Proc Natl Acad Sci 79:3423–3427PubMedGoogle Scholar
  76. Polster BM, Basanez G, Etxebarria A, Hardwick JM, Nicholls DG (2005) Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem 280:6447–6454PubMedGoogle Scholar
  77. Potaman VN, Shlyakhtenko LS, Oussatcheva EA, Lyubchenko YL, Soldatenkov VA (2005) Specific binding of poly(ADP-ribose) polymerase-1 to cruciform hairpins. J Mol Biol 348:609–615PubMedGoogle Scholar
  78. Satoh M, Date I, Nakajima M, Takahashi K, Iseda K, Tamiya T, Ohmoto T, Ninomiya Y, Asari S (2001) Inhibition of poly(ADP-ribose) polymerase attenuates cerebral vasospasm after subarachnoid hemorrhage in rabbits. Stroke 32:225–231PubMedGoogle Scholar
  79. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedGoogle Scholar
  80. Schmid G, Wang ZQ, Wesierska-Gadek J (1999) Compensatory expression of p73 in PARP-deficient mouse fibroblast as response to reduced level of regularly spliced wild-type p53. Biochem Biophys Res Comm 255:399–405PubMedGoogle Scholar
  81. Schreiber V, Ame JC, Dolle P, Schultz I, Rinaldi B, Fraulob V, Menissier-de Murcia J, de Murcia G (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036PubMedGoogle Scholar
  82. Schreiber V, Hunting D, Trucco C, Gowans B, Grunwald D, de Murcia G, de Murcia JM (1995) A dominant-negative mutant of human poly(ADP-ribose) polymerase affects cell recovery, apoptosis, and sister chromatid exchange following DNA damage. Proc Natl Acad Sci USA 92:4753–4757PubMedGoogle Scholar
  83. Scott GS, Hake P, Kean RB, Virag L, Szabo C, Hooper DC (2001) Role of poly(ADP-ribose) synthetase activation in the development of experimental allergic encephalomyelitis. J Neuroimm 117:78–86Google Scholar
  84. Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares AH, Smulson ME (1998) Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis. J Biol Chem 273:13703–13712PubMedGoogle Scholar
  85. Skaper SD (2003a) Poly(ADP-Ribose) polymerase-1 in acute neuronal death and inflammation: a strategy for neuroprotection. Ann N Y Acad Sci 993:217–228PubMedGoogle Scholar
  86. Skaper SD (2003b) Poly(ADP-ribosyl)ation enzyme-1 as a target for neuroprotection in acute central nervous system injury. Curr Drug Targets CNS Neurol Disord 2:279–291PubMedGoogle Scholar
  87. Slattery E, Dignam JD, Matsui T, Roeder RG (1983) Purification and analysis of a factor which suppresses nick-induced transcription by RNA polymerase II and its identity with poly(ADP-ribose) polymerase. J Biol Chem 285:5955–5959Google Scholar
  88. Smith S (2001) The world according to PARP. Trends Biochem Sci 26:174–179PubMedGoogle Scholar
  89. Southan GJ, Szabo C (2003) Poly(ADP-ribose) polymerase inhibitors. Curr Med Chem 10:321–340PubMedGoogle Scholar
  90. Strosznajder RP, Gadamski R, Czapski GA, Jesko H, Strosznajder JB (2003) Poly(ADP-ribose) polymerase during reperfusion after transient forebrain ischemia: its role in brain edema and cell death. J Mol Neurosci 20:61–72PubMedGoogle Scholar
  91. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446PubMedGoogle Scholar
  92. Szabo C, Dawson VL (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287–298PubMedGoogle Scholar
  93. Takahashi K, Greenberg JH (1999) The effect of reperfusion on neuroprotection using an inhibitor of poly(ADP-ribose) polymerase. NeuroReport 10:1017–1022Google Scholar
  94. Takahashi K, Greenberg JH, Jackson P, Maclin K, Zhang J (1997) Neuroprotective effects of inhibiting poly(ADP-ribose) synthetase on focal cerebral ischemia in rats. J Cereb Blood Flow Metab 17:1137–1142PubMedGoogle Scholar
  95. Takahashi K, Piper AA, Croul SE, Zhang J, Snyder SH, Greenberg JH (1999) Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. Brain Res 829(1–2):46–54PubMedGoogle Scholar
  96. Tokime T, Nozaki K, Sugino T, Kikuchi H, Hashimoto N, Ueda K (1998) Enhanced poly(ADP-ribosyl)ation after focal ischemia in rat brain. J Cereb Blood Flow Metab 18:991–997PubMedGoogle Scholar
  97. Tong WM, Cortes U, Wang ZQ (2001) Poly(ADP-ribose) polymerase: a guardian angel protecting the genome and suppressing tumorigenesis. Biochim Biophys Acta 1552:27–37PubMedGoogle Scholar
  98. Ullrich O, Diestel A, Bechmann I, Homberg M, Grune T, Hass R, Nitsch R (2001a) Turnover of oxidatively damaged nuclear proteins in BV-2 microglial cells is linked to their activation state by poly(ADP-ribosyl)ation. FASEB J 15:1460–1462PubMedGoogle Scholar
  99. Ullrich O, Diestel A, Eyupoglu IY, Nitsch R (2001b) Regulation of microglial expression of integrins by poly(ADP-ribose) polymerase-1. Nat Cell Biol 3:1035–1042PubMedGoogle Scholar
  100. Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429PubMedGoogle Scholar
  101. Wang H, Yu SW, Poitras MF, Norris J, Poirier GG, Dawson TM, Dawson VL (2003) Poly(ADP-ribose) polymer serves as a death signal by triggering apoptosis-inducing factor release. Soc Neurosci Abstr 34:1232Google Scholar
  102. Wang X, Ohnishi K, Takahashi A, Ohnishi T (1998) Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation. Oncogene 17:2819–2825PubMedGoogle Scholar
  103. Wesierska-Gadek J, Schid G, Cerni C (1996) ADP-ribosylation of wilde-type p53 in vitro: binding of p53 to specific p53-consensus sequence prevents its modification. Biochem Biophys Res Comm 224:96–102PubMedGoogle Scholar
  104. Wesierska-Gadek J, Schmid G (2000) Overexpressed poly(ADP-ribose) polymerase dealys the relase of rat cells from p53-mediated G(1) checkpoint. J Cell Biochem 80:85–103PubMedGoogle Scholar
  105. Whalen MJ, Clark RS, Dixon CE, Robichaud P, Marion DW, Vagni V, Graham SH, Virag L, Hasko G, Stachlewitz R, Szabo C, Kochanek PM (1999) Reduction of cognitive and motor deficits after traumatic brain injury in mice deficient in poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 19:835–842PubMedGoogle Scholar
  106. Yang J, Klaidman LK, Nalbandian A, Oliver J, Chang ML, Chan PH, Adams JD Jr (2002) The effects of nicotinamide on energy metabolism following transient focal cerebral ischemia in Wistar rats. Neurosci Lett 333:91–94PubMedGoogle Scholar
  107. Ying W, Chen Y, Alano CC, Swanson RA (2002) Tricarboxylic acid cycle substrates prevent PARP-mediated death of neurons and astrocytes. J Cereb Blood Flow Metab 22:774–779PubMedGoogle Scholar
  108. Yu SW, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263PubMedGoogle Scholar
  109. Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H, Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem 86:306–317PubMedGoogle Scholar
  110. Ziegler M, Oei SL (2001) A cellular survival switch: poly(ADP-ribosyl)ation stimulates DNA repair and silences transcription. BioEssay 23:543–548Google Scholar
  111. Zingarelli B, Hake PW, O’Connor M, Denenberg A, Wong HR, Kong S, Aronow BJ (2004) Differential regulation of activator protein-1 and heat shock factor-1 in myocardial ischemia and reperfusion injury: role of poly(ADP-ribose) polymerase-1. Am J Physiol Heart Circ Physiol 286:H1408–H1415PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Preclinical and Clinical PharmacologyUniversity of FlorenceFlorenceItaly

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