DNA Damage and Repair in the Brain: Implications for Seizure-Induced Neuronal Injury, Endangerment, and Neuroprotection

  • Samantha L. Crowe
  • Alexei D. Kondratyev


Continuous seizures can be induced in rodents using several methods, including focal or systemic chemoconvulsants or electrical stimulation of particular neural networks. Injurious durations of seizure activity result in neuronal death in vulnerable brain regions, including the hippocampal CA1 and CA3 subfields and hilus; the entorhinal, perirhinal, and piriform cortices; and the amygdala, regardless of the method employed to evoke the seizures (Ben-Ari et al. 1986; Du et al. 1995; Fujikawa 1996; Fujikawa et al. 2000a, b; Henshall et al. 2000; Kondratyev et al. 2001; Motte et al. 1998; Schwob et al. 1980; Sloviter et al. 1996; Sperk et al. 1983). Other neuronal populations, including those located in striatum, in the hippocampal CA2 subfield, and in the hippocampal dentate granule cell layer, are resistant to seizure-evoked injury. It is unclear why particular endangered populations die in the aftermath of injurious seizures, whereas other populations survive. One plausible explanation is that injury-resistant populations are either inherently endowed with or more efficiently engage protective cellular mechanisms.

Although the exact factors mediating the transition from cell endangerment to cell death following seizures are unknown, it is generally accepted that seizure-induced cellular damage significantly contributes to injury (i.e., frank neuronal death). It is well established that the cellular damage caused by continuous seizures increases with seizure duration, and it is generally believed that seizures lasting in excess of 30 min in duration are required to elicit injury (Fujikawa 1996; Henshall et al. 2000; Kondratyev and Gale 2001) (Fig. 16.1a). Such seizures are thus considered to be “injurious.” Shorter seizure durations, although likely to evoke some degree of cellular damage, are subthreshold for inducing cell death and are thus defined here as being “noninjurious.” Given that endangered neurons survive ­noninjurious seizure durations (i.e., durations not eliciting frank neuronal death), it is plausible that the cellular damage elicited by these seizures does not reach the threshold necessary for triggering cell death and/or compensatory repair processes are both activated in response to and sufficient for survival.


Fluorescence Resonance Energy Transfer Nucleotide Excision Repair Ischemic Precondition Base Excision Repair Seizure Duration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Drs Susette Mueller and Xuehua Xu from the Lombardi Comprehensive Cancer Center Microscopy & Imaging Shared Resource for their contribution to obtaining confocal imaging and FRET analysis. The authors thank Dr Maryam Khafizova for technical assistance with neuronal cultures and immunocytochemistry. The previously unpublished studies presented here were supported by the NIH grants MH 02040, NS 048974 and subcontract to AG019165 (AK), T32-NS041231, and the NIH predoctoral fellowship NS 046199 (SC).


  1. Aguirre N, Beal MF, Matson WR, Bogdanov MB (2005) Increased oxidative damage to DNA in an animal model of amyotrophic lateral sclerosis. Free Radic Res 39:383–388PubMedCrossRefGoogle Scholar
  2. Ahnesorg P, Smith P, Jackson SP (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124:301–313PubMedCrossRefGoogle Scholar
  3. Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69:1196–1203PubMedCrossRefGoogle Scholar
  4. An SJ, Kang TC, Park SK, Hwang IK, Cho SS, Chung MH, Won MH (2002) Oxidative DNA damage and alteration of glutamate transporter expressions in the hippocampal Ca1 area immediately after ischemic insult. Mol Cells 13:476–480PubMedGoogle Scholar
  5. Anderson L, Henderson C, Adachi Y (2001) Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol Cell Biol 21:1719–1729PubMedCrossRefGoogle Scholar
  6. Araneda S, Mermet N, Verjat T, Angulo JF, Radicella JP (2001) Expression of Kin17 and 8-OxoG DNA glycosylase in cells of rodent and quail central nervous system. Brain Res Bull 56:139–146PubMedCrossRefGoogle Scholar
  7. Arnett SD, Osbourn DM, Moore KD, Vandaveer SS, Lunte CE (2005) Determination of 8-oxoguanine and 8-hydroxy-2′-deoxyguanosine in the rat cerebral cortex using microdialysis sampling and capillary electrophoresis with electrochemical detection. J Chromatogr B Analyt Technol Biomed Life Sci 827:16–25PubMedCrossRefGoogle Scholar
  8. Barichello T, Bonatto F, Agostinho FR, Reinke A, Moreira JC, Dal-Pizzol F, Izquierdo I, Quevedo J (2004a) Structure-related oxidative damage in rat brain after acute and chronic electroshock. Neurochem Res 29:1749–1753PubMedCrossRefGoogle Scholar
  9. Barichello T, Bonatto F, Feier G, Martins MR, Moreira JC, Dal-Pizzol F, Izquierdo I, Quevedo J (2004b) No evidence for oxidative damage in the hippocampus after acute and chronic electroshock in rats. Brain Res 1014:177–183PubMedCrossRefGoogle Scholar
  10. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214PubMedCrossRefGoogle Scholar
  11. Bazan NG, Birkle DL, Tang W, Reddy TS (1986) The accumulation of free arachidonic acid, diacylglycerols, prostaglandins, and lipoxygenase reaction products in the brain during experimental epilepsy. Adv Neurol 44:879–902PubMedGoogle Scholar
  12. Bellissimo MI, Amado D, Abdalla DS, Ferreira EC, Cavalheiro EA, Naffah-Mazzacoratti MG (2001) Superoxide dismutase, glutathione peroxidase activities and the hydroperoxide concentration are modified in the hippocampus of epileptic rats. Epilepsy Res 46:121–128PubMedCrossRefGoogle Scholar
  13. Belloni M, Uberti D, Rizzini C, Ferrari-Toninelli G, Rizzonelli P, Jiricny J, Spano P, Memo M (1999) Distribution and kainate-mediated induction of the DNA mismatch repair protein MSH2 in rat brain. Neuroscience 94:1323–1331PubMedCrossRefGoogle Scholar
  14. Ben-Ari Y, Repressa A, Tremblay E, Nitecka L (1986) Selective and non-selective seizure related brain damage produced by kainic acid. Adv Exp Med Biol 203:647–657PubMedGoogle Scholar
  15. Bishnoi M, Patil CS, Kumar A, Kulkarni SK (2007) Co-administration of acetyl-11-keto-beta-boswellic acid, a specific 5-lipoxygenase inhibitor, potentiates the protective effect of COX-2 inhibitors in kainic acid-induced neurotoxicity in mice. Pharmacology 79(1):34–41PubMedCrossRefGoogle Scholar
  16. Bladen CL, Udayakumar D, Takeda Y, Dynan WS (2005) Identification of the polypyrimidine tract binding protein-associated splicing factor.p54(nrb) complex as a candidate DNA double-strand break rejoining factor. J Biol Chem 280:5205–5210PubMedCrossRefGoogle Scholar
  17. Bogdanov M, Brown RH, Matson W, Smart R, Hayden D, O’Donnell H, Flint BM, Cudkowicz M (2000) Increased oxidative damage to DNA in ALS patients. Free Radic Biol Med 29:652–658PubMedCrossRefGoogle Scholar
  18. Bouquet F, Muller C, Salles B (2006) The loss of gammaH2AX signal is a marker of DNA double strand breaks repair only at low levels of DNA damage. Cell Cycle 5:1116–1122PubMedCrossRefGoogle Scholar
  19. Brooks PJ (1998) Detection of excision nuclease in cell-free extracts from the adult mammalian brain. Mutat Res 408:37–46PubMedGoogle Scholar
  20. Brooks PJ (2002) DNA repair in neural cells: basic science and clinical implications. Mutat Res 509:93–108PubMedGoogle Scholar
  21. Brooks PJ, Marietta C, Goldman D (1996) DNA mismatch repair and DNA methylation in adult brain neurons. J Neurosci 16:939–945PubMedGoogle Scholar
  22. Bruce AJ, Baudry M (1995) Oxygen free radicals in rat limbic structures after kainate-induced seizures. Free Radic Biol Med 18:993–1002PubMedCrossRefGoogle Scholar
  23. Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, Plebani A, Stephan JL, Hufnagel M, le Deist F, Fischer A, Durandy A, de Villartay JP, Revy P (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124:287–299PubMedCrossRefGoogle Scholar
  24. Cardozo-Pelaez F, Song S, Parthasarathy A, Hazzi C, Naidu K, Sanchez-Ramos J (1999) Oxidative DNA damage in the aging mouse brain. Mov Disord 14:972–980PubMedCrossRefGoogle Scholar
  25. Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 5:675–679PubMedCrossRefGoogle Scholar
  26. Chechlacz M, Vemuri MC, Naegele JR (2001) Role of DNA-dependent protein kinase in neuronal survival. J Neurochem 78:141–154PubMedCrossRefGoogle Scholar
  27. Chen J, Uchimura K, Stetler RA, Zhu RL, Nakayama M, Jin K, Graham SH, Simon RP (1998) Transient global ischemia triggers expression of the DNA damage-inducible gene GADD45 in the rat brain. J Cereb Blood Flow Metab 18:646–657PubMedCrossRefGoogle Scholar
  28. Chen L, Trujillo K, Sung P, Tomkinson AE (2000) Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J Biol Chem 275:26196–26205PubMedCrossRefGoogle Scholar
  29. Chen D, Minami M, Henshall DC, Meller R, Kisby G, Simon RP (2003) Upregulation of mitochondrial base-excision repair capability within rat brain after brief ischemia. J Cereb Blood Flow Metab 23:88–98PubMedCrossRefGoogle Scholar
  30. Cheng WH, von Kobbe C, Opresko PL, Arthur LM, Komatsu K, Seidman MM, Carney JP, Bohr VA (2004) Linkage between Werner syndrome protein and the Mre11 complex via Nbs1. J Biol Chem 279:21169–21176PubMedCrossRefGoogle Scholar
  31. Chinopoulos C, Adam-Vizi V (2006) Calcium, mitochondria and oxidative stress in neuronal pathology. Novel aspects of an enduring theme. FEBS J 273:433–450PubMedCrossRefGoogle Scholar
  32. Chuang YC, Chang AY, Lin JW, Hsu SP, Chan SH (2004) Mitochondrial dysfunction and ultrastructural damage in the hippocampus during kainic acid-induced status epilepticus in the rat. Epilepsia 45:1202–1209PubMedCrossRefGoogle Scholar
  33. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Sigel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry: molecular, cellular, and medical aspects. Lippincott-Raven, Philadelphia, pp 637–669Google Scholar
  34. Cock HR, Tong X, Hargreaves IP, Heales SJ, Clark JB, Patsalos PN, Thom M, Groves M, Schapira AH, Shorvon SD, Walker MC (2002) Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat. Epilepsy Res 48:157–168PubMedCrossRefGoogle Scholar
  35. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695PubMedCrossRefGoogle Scholar
  36. Crowe SL, Movsesyan VA, Jorgensen TJ, Kondratyev A (2006) Rapid phosphorylation of histone H2A.X following ionotropic glutamate receptor activation. Eur J Neurosci 23:2351–2361PubMedCrossRefGoogle Scholar
  37. Cui J, Holmes EH, Liu PK (1999) Oxidative damage to the c-fos gene and reduction of its transcription after focal cerebral ischemia. J Neurochem 73:1164–1174PubMedCrossRefGoogle Scholar
  38. Cui J, Holmes EH, Greene TG, Liu PK (2000) Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain. FASEB J 14:955–967PubMedGoogle Scholar
  39. Culmsee C, Bondada S, Mattson MP (2001) Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity. Brain Res Mol Brain Res 87:257–262PubMedCrossRefGoogle Scholar
  40. Dal Pizzol F, Quevedo J, Streck E, Walz R, Moreira JC (2007) Changes in lipid composition in hippocampus early and late after status epilepticus induced by kainic acid in wistar rats. Metab Brain Dis 22:25–29PubMedCrossRefGoogle Scholar
  41. Davydov V, Hansen LA, Shackelford DA (2003) Is DNA repair compromised in Alzheimer’s disease? Neurobiol Aging 24:953–968PubMedCrossRefGoogle Scholar
  42. de Vos M, Hayward B, Bonthron DT, Sheridan E (2005) Phenotype associated with recessively inherited mutations in DNA mismatch repair (MMR) genes. Biochem Soc Trans 33:718–720PubMedCrossRefGoogle Scholar
  43. Dringen R, Hirrlinger J (2003) Glutathione pathways in the brain. Biol Chem 384:505–516PubMedCrossRefGoogle Scholar
  44. Dringen R, Kussmaul L, Hamprecht B (1998) Detoxification of exogenous hydrogen peroxide and organic hydroperoxides by cultured astroglial cells assessed by microtiter plate assay. Brain Res Brain Res Protoc 2:223–228PubMedCrossRefGoogle Scholar
  45. Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79:157–165PubMedCrossRefGoogle Scholar
  46. Du F, Eid T, Lothman EW, Kohler C, Schwarcz R (1995) Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy. J Neurosci 15:6301–6313PubMedGoogle Scholar
  47. Dynan WS, Yoo S (2002) Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res 26(7):1551–1559CrossRefGoogle Scholar
  48. Edwards M, Rassin DK, Izumi T, Mitra S, Perez-Polo JR (1998) APE/Ref-1 responses to oxidative stress in aged rats. J Neurosci Res 54:635–638PubMedCrossRefGoogle Scholar
  49. Endres M, Biniszkiewicz D, Sobol RW, Harms C, Ahmadi M, Lipski A, Katchanov J, Mergenthaler P, Dirnagl U, Wilson SH, Meisel A, Jaenisch R (2004) Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase. J Clin Invest 113:1711–1721PubMedGoogle Scholar
  50. Englander EW, Ma H (2006) Differential modulation of base excision repair activities during brain ontogeny: implications for repair of transcribed DNA. Mech Ageing Dev 127:64–69PubMedCrossRefGoogle Scholar
  51. Englander EW, Greeley GH Jr, Wang G, Perez-Polo JR, Lee HM (1999) Hypoxia-induced mitochondrial and nuclear DNA damage in the rat brain. J Neurosci Res 58:262–269PubMedCrossRefGoogle Scholar
  52. Enokido Y, Inamura N, Araki T, Satoh T, Nakane H, Yoshino M, Nakatsu Y, Tanaka K, Hatanaka H (1997) Loss of the xeroderma pigmentosum group A gene (XPA) enhances apoptosis of cultured cerebellar neurons induced by UV but not by low-K+ medium. J Neurochem 69:246–251PubMedCrossRefGoogle Scholar
  53. Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A (2004) H2AX: the histone guardian of the genome. DNA Repair (Amst) 3:959–967CrossRefGoogle Scholar
  54. Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, Kowall NW, Brown RH Jr, Beal MF (1997) Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 69:2064–2074PubMedCrossRefGoogle Scholar
  55. Francisconi S, Codenotti M, Ferrari TG, Uberti D, Memo M (2006) Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair. J Neurochem 98:223–233PubMedCrossRefGoogle Scholar
  56. Friedberg EC, Walker GC, Siede W (1995) DNA repair and mutagenesis. ASM Press, Washington, DCGoogle Scholar
  57. Friesner JD, Liu B, Culligan K, Britt AB (2005) Ionizing radiation-dependent gamma-H2AX focus formation requires ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3-related. Mol Biol Cell 16:2566–2576PubMedCrossRefGoogle Scholar
  58. Fujikawa DG (1996) The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res 725:11–22PubMedGoogle Scholar
  59. Fujikawa DG, Shinmei SS, Cai B (2000a) Kainic acid-induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: implications for programmed cell death mechanisms. Neuroscience 98:41–53PubMedCrossRefGoogle Scholar
  60. Fujikawa DG, Shinmei SS, Cai B (2000b) Seizure-induced neuronal necrosis: implications for programmed cell death mechanisms. Epilepsia 41(Suppl 6):S9–S13PubMedCrossRefGoogle Scholar
  61. Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH (1999a) Early decrease of apurinic/apyrimidinic endonuclease expression after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 19:495–501PubMedCrossRefGoogle Scholar
  62. Fujimura M, Morita-Fujimura Y, Narasimhan P, Copin JC, Kawase M, Chan PH (1999b) Copper-zinc superoxide dismutase prevents the early decrease of apurinic/apyrimidinic endonuclease and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke 30:2408–2415PubMedGoogle Scholar
  63. Fujimura M, Morita-Fujimura Y, Sugawara T, Chan PH (1999c) Early decrease of XRCC1, a DNA base excision repair protein, may contribute to DNA fragmentation after transient focal cerebral ischemia in mice. Stroke 30:2456–2462PubMedGoogle Scholar
  64. Fujimura M, Morita-Fujimura Y, Noshita N, Yoshimoto T, Chan PH (2000) Reduction of the DNA base excision repair protein, XRCC1, may contribute to DNA fragmentation after cold injury-induced brain trauma in mice. Brain Res 869:105–111PubMedCrossRefGoogle Scholar
  65. Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040PubMedCrossRefGoogle Scholar
  66. Gobbel GT, Bellinzona M, Vogt AR, Gupta N, Fike JR, Chan PH (1998) Response of postmitotic neurons to X-irradiation: implications for the role of DNA damage in neuronal apoptosis. J Neurosci 18:147–155PubMedGoogle Scholar
  67. Gordon GW, Berry G, Liang XH, Levine B, Herman B (1998) Quantitative fluorescence resonance energy transfer measurements using fluorescence microscopy. Biophys J 74:2702–2713PubMedCrossRefGoogle Scholar
  68. Gupta YK, Briyal S (2006) Protective effect of vineatrol against kainic acid induced seizures, oxidative stress and on the expression of heat shock proteins in rats. Eur Neuropsychopharmacol 16:85–91PubMedCrossRefGoogle Scholar
  69. Gupta YK, Gupta M, Kohli K (2003) Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol 47:373–386PubMedGoogle Scholar
  70. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A (2001) Does oxidative damage to DNA increase with age? Proc Natl Acad Sci USA 98:10469–10474PubMedCrossRefGoogle Scholar
  71. Hammarsten O, Chu G (1998) DNA-dependent protein kinase: DNA binding and activation in the absence of Ku. Proc Natl Acad Sci USA 95:525–530PubMedCrossRefGoogle Scholar
  72. Hayashi T, Sakurai M, Itoyama Y, Abe K (1999) Oxidative damage and breakage of DNA in rat brain after transient MCA occlusion. Brain Res 832:159–163PubMedCrossRefGoogle Scholar
  73. Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R, Tamagawa K (2004) Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. J Neuropathol Exp Neurol 63:1048–1057PubMedGoogle Scholar
  74. Hegde MR, Chong B, Blazo ME, Chin LH, Ward PA, Chintagumpala MM, Kim JY, Plon SE, Richards CS (2005) A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res 11:4689–4693PubMedCrossRefGoogle Scholar
  75. Hegde ML, Gupta VB, Anitha M, Harikrishna T, Shankar SK, Muthane U, Subba RK, Jagannatha Rao KS (2006) Studies on genomic DNA topology and stability in brain regions of Parkinson’s disease. Arch Biochem Biophys 449:143–156PubMedCrossRefGoogle Scholar
  76. Henshall DC, Sinclair J, Simon RP (1999) Relationship between seizure-induced transcription of the DNA damage-inducible gene GADD45, DNA fragmentation, and neuronal death in focally evoked limbic epilepsy. J Neurochem 73:1573–1583PubMedCrossRefGoogle Scholar
  77. Henshall DC, Sinclair J, Simon RP (2000) Spatio-temporal profile of DNA fragmentation and its relationship to patterns of epileptiform activity following focally evoked limbic seizures. Brain Res 858:290–302PubMedCrossRefGoogle Scholar
  78. Hermann DM, Kuroiwa T, Hata R, Gillardon F, Ito U, Mies G (2001) Expression of redox factor-1, p53-activated gene 608 and caspase-3 messenger RNAs following repeated unilateral common carotid artery occlusion in gerbils – relationship to delayed cell injury and secondary failure of energy state. Neuroscience 102:779–787PubMedCrossRefGoogle Scholar
  79. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 64:9152–9159PubMedCrossRefGoogle Scholar
  80. Huang J, Dynan WS (2002) Reconstitution of the mammalian DNA double-strand break end-joining reaction reveals a requirement for an Mre11/Rad50/NBS1-containing fraction. Nucleic Acids Res 30:667–674PubMedCrossRefGoogle Scholar
  81. Intano GW, Cho EJ, McMahan CA, Walter CA (2003) Age-related base excision repair activity in mouse brain and liver nuclear extracts. J Gerontol A Biol Sci Med Sci 58:205–211PubMedGoogle Scholar
  82. Itoh M, Hayashi M, Shioda K, Minagawa M, Isa F, Tamagawa K, Morimatsu Y, Oda M (1999) Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 21:326–333PubMedCrossRefGoogle Scholar
  83. Jackson SP (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis 23(5):687–696PubMedCrossRefGoogle Scholar
  84. Jeggo P, O’Neill P (2002) The Greek Goddess, Artemis, reveals the secrets of her cleavage. DNA Repair (Amst) 1:771–777CrossRefGoogle Scholar
  85. Kajitani K, Yamaguchi H, Dan Y, Furuichi M, Kang D, Nakabeppu Y (2006) MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity. J Neurosci 26:1688–1698PubMedCrossRefGoogle Scholar
  86. Karahalil B, Hogue BA, de Souza-Pinto NC, Bohr VA (2002) Base excision repair capacity in mitochondria and nuclei: tissue-specific variations. FASEB J 16:1895–1902PubMedCrossRefGoogle Scholar
  87. Karran P, Bignami M (1999) Mismatch repair and cancer. In: Smith PJ, Jones CJ (eds) DNA recombination and repair. Oxford, Oxford University Press, pp 66–98Google Scholar
  88. Kato H, Liu Y, Araki T, Kogure K (1991) Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protection effects. Brain Res 553:238–242PubMedCrossRefGoogle Scholar
  89. Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH (2005) Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 1050:130–137PubMedCrossRefGoogle Scholar
  90. Kawase M, Fujimura M, Morita-Fujimura Y, Chan PH (1999) Reduction of apurinic/apyrimidinic endonuclease expression after transient global cerebral ischemia in rats: implication of the failure of DNA repair in neuronal apoptosis. Stroke 30:441–448PubMedGoogle Scholar
  91. Kelly ME, McIntyre DC (1994) Hippocampal kindling protects several structures from the neuronal damage resulting from kainic acid-induced status epilepticus. Brain Res 634:245–256PubMedCrossRefGoogle Scholar
  92. Khan A, Lai H, Nishimura Y, Mirolo MH, Singh NP (1995) Effects of ECS on DNA single-strand breaks in rat brain cells. Convuls Ther 11:114–121PubMedGoogle Scholar
  93. Kim H, Bing G, Jhoo W, Ko KH, Kim WK, Suh JH, Kim SJ, Kato K, Hong JS (2000) Changes of hippocampal Cu/Zn-superoxide dismutase after kainate treatment in the rat. Brain Res. 853:215–226PubMedCrossRefGoogle Scholar
  94. Kim GW, Noshita N, Sugawara T, Chan PH (2001) Early decrease in DNA repair proteins, Ku 70 and Ku86, and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke 32:1401–1407PubMedGoogle Scholar
  95. Kim SJ, Kim JE, Moon IS (2004) Paraquat induces apoptosis of cultured rat cortical cells. Mol Cells 17:102–107PubMedGoogle Scholar
  96. Kisby GE, Milne J, Sweatt C (1997) Evidence of reduced DNA repair in amyotrophic lateral sclerosis brain tissue. Neuroreport 8:1337–1340PubMedCrossRefGoogle Scholar
  97. Kisby GE, Lesselroth H, Olivas A, Samson L, Gold B, Tanaka K, Turker MS (2004) Role of nucleotide- and base-excision repair in genotoxin-induced neuronal cell death. DNA Repair (Amst) 3:617–627Google Scholar
  98. Kohji T, Hayashi M, Shioda K, Minagawa M, Morimatsu Y, Tamagawa K, Oda M (1998) Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci Lett 243:133–136PubMedCrossRefGoogle Scholar
  99. Kondratyev A, Gale K (2001) Temporal and spatial patterns of DNA fragmentation following focally or systemically-evoked status epilepticus in rats. Neurosci Lett 310:13–16PubMedCrossRefGoogle Scholar
  100. Kondratyev A, Sahibzada N, Gale K (2001) Electroconvulsive shock exposure prevents neuronal apoptosis after kainic acid-evoked status epilepticus. Brain Res Mol Brain Res 91:1–13PubMedCrossRefGoogle Scholar
  101. Krishna TH, Mahipal S, Sudhakar A, Sugimoto H, Kalluri R, Rao KS (2005) Reduced DNA gap repair in aging rat neuronal extracts and its restoration by DNA polymerase beta and DNA-ligase. J Neurochem 92:818–823PubMedCrossRefGoogle Scholar
  102. Krokan HE, Nilsen H, Skorpen F, Otterlei M, Slupphaug G (2000) Base excision repair of DNA in mammalian cells. FEBS Lett 476:73–77PubMedCrossRefGoogle Scholar
  103. Kruhlak MJ, Celeste A, Dellaire G, Fernandez-Capetillo O, Muller WG, McNally JG, Bazett-Jones DP, Nussenzweig A (2006) Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks. J Cell Biol 172:823–834PubMedCrossRefGoogle Scholar
  104. Kruman II, Schwartz E, Kruman Y, Cutler RG, Zhu X, Greig NH, Mattson MP (2004) Suppression of uracil-DNA glycosylase induces neuronal apoptosis. J Biol Chem 279:43952–43960PubMedCrossRefGoogle Scholar
  105. Kubota Y, Nash RA, Klungland A, Schar P, Barnes DE, Lindahl T (1996) Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. EMBO J 15:6662–6670PubMedGoogle Scholar
  106. Lan J, Henshall DC, Simon RP, Chen J (2000) Formation of the base modification 8-hydroxyl-2′-deoxyguanosine and DNA fragmentation following seizures induced by systemic kainic acid in the rat. J Neurochem 74:302–309PubMedCrossRefGoogle Scholar
  107. Lan J, Li W, Zhang F, Sun FY, Nagayama T, O’Horo C, Chen J (2003) Inducible repair of oxidative DNA lesions in the rat brain after transient focal ischemia and reperfusion. J Cereb Blood Flow Metab 23:1324–1339PubMedCrossRefGoogle Scholar
  108. Laposa RR, Cleaver JE (2001) DNA repair on the brain. Proc Natl Acad Sci USA 98:12860–12862PubMedCrossRefGoogle Scholar
  109. Lee HM, Wang C, Hu Z, Greeley GH, Makalowski W, Hellmich HL, Englander EW (2002) Hypoxia induces mitochondrial DNA damage and stimulates expression of a DNA repair enzyme, the Escherichia coli MutY DNA glycosylase homolog (MYH), in vivo, in the rat brain. J Neurochem 80:928–937PubMedCrossRefGoogle Scholar
  110. Lewen A, Sugawara T, Gasche Y, Fujimura M, Chan PH (2001) Oxidative cellular damage and the reduction of APE/Ref-1 expression after experimental traumatic brain injury. Neurobiol Dis 8:380–390PubMedCrossRefGoogle Scholar
  111. Li B, Comai L (2000) Functional interaction between Ku and the Werner syndrome protein in DNA end processing. J Biol Chem 275:39800PubMedGoogle Scholar
  112. Li S, Zheng J, Carmichael ST (2005) Increased oxidative protein and DNA damage but decreased stress response in the aged brain following experimental stroke. Neurobiol Dis 18:432–440PubMedCrossRefGoogle Scholar
  113. Li W, Luo Y, Zhang F, Signore AP, Gobbel GT, Simon RP, Chen J (2006) Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. J Cereb Blood Flow Metab 26:181–198PubMedCrossRefGoogle Scholar
  114. Liang LP, Ho YS, Patel M (2000) Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 101:563–570PubMedCrossRefGoogle Scholar
  115. Lin LH, Cao S, Yu L, Cui J, Hamilton WJ, Liu PK (2000) Up-regulation of base excision repair activity for 8-hydroxy-2′-deoxyguanosine in the mouse brain after forebrain ischemia-reperfusion. J Neurochem 74:1098–1105PubMedCrossRefGoogle Scholar
  116. Ling X, Zhang LM, Huang YL, Bao WL, Sun FY (1999) Neuronal ERCC6 mRNA expression in rat brain induced by a transient focal cerebral ischemia. Zhongguo Yao Li Xue Bao 20:15–20PubMedGoogle Scholar
  117. Liu PK, Hsu CY, Dizdaroglu M, Floyd RA, Kow YW, Karakaya A, Rabow LE, Cui JK (1996) Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion. J Neurosci 16:6795–6806PubMedGoogle Scholar
  118. Lovell MA, Gabbita SP, Markesbery WR (1999) Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J Neurochem 72:771–776PubMedCrossRefGoogle Scholar
  119. Lovell MA, Xie C, Markesbery WR (2000) Decreased base excision repair and increased helicase activity in Alzheimer’s disease brain. Brain Res 855:116–123PubMedCrossRefGoogle Scholar
  120. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891PubMedCrossRefGoogle Scholar
  121. Ma Y, Lu H, Tippin B, Goodman MF, Shimazaki N, Koiwai O, Hsieh CL, Schwarz K, Lieber MR (2004) A biochemically defined system for mammalian nonhomologous DNA end joining. Mol Cell 16:701–713PubMedCrossRefGoogle Scholar
  122. Ma Y, Schwarz K, Lieber MR (2005) The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair (Amst) 4:845–851CrossRefGoogle Scholar
  123. MacGregor DG, Higgins MJ, Jones PA, Maxwell WL, Watson MW, Graham DI, Stone TW (1996) Ascorbate attenuates the systemic kainate-induced neurotoxicity in the rat hippocampus. Brain Res 727:133–144PubMedCrossRefGoogle Scholar
  124. Marietta C, Palombo F, Gallinari P, Jiricny J, Brooks PJ (1998) Expression of long-patch and short-patch DNA mismatch repair proteins in the embryonic and adult mammalian brain. Brain Res Mol Brain Res 53:317–320PubMedCrossRefGoogle Scholar
  125. Masco D, Sahibzada N, Gale K (1995) Electroconvulsive shock prevents apoptotic and excitotoxic cell death. Proc Soc Neurosci 21:326.12Google Scholar
  126. McMurray CT (2005) To die or not to die: DNA repair in neurons. Mutat Res 577:260–274PubMedGoogle Scholar
  127. Meira LB, Devaraj S, Kisby GE, Burns DK, Daniel RL, Hammer RE, Grundy S, Jialal I, Friedberg EC (2001) Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress. Cancer Res 61:5552–5557PubMedGoogle Scholar
  128. Mendez DR, Cherian L, Moore N, Arora T, Liu PK, Robertson CS (2004) Oxidative DNA lesions in a rodent model of traumatic brain injury. J Trauma 56:1235–1240PubMedCrossRefGoogle Scholar
  129. Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ (2004) A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer. Fam Cancer 3:123–127PubMedCrossRefGoogle Scholar
  130. Merlo D, Di Stasi AMM, Bonini P, Mollinari C, Cardinale A, Cozzolino F, Wisden W, Garaci E (2005) DNA repair in post-mitotic neurons: a gene-trapping strategy. Cell Death Differ 12:307–309PubMedCrossRefGoogle Scholar
  131. Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M (2003) Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosci Lett 337:56–60PubMedCrossRefGoogle Scholar
  132. Morita-Fujimura Y, Fujimura M, Kawase M, Chan PH (1999) Early decrease in apurinic/apyrimidinic endonuclease is followed by DNA fragmentation after cold injury-induced brain trauma in mice. Neuroscience 93:1465–1473PubMedCrossRefGoogle Scholar
  133. Motte J, Fernandes MJ, Baram TZ, Nehlig A (1998) Spatial and temporal evolution of neuronal activation, stress and injury in lithium-pilocarpine seizures in adult rats. Brain Res 793:61–72PubMedCrossRefGoogle Scholar
  134. Nagayama T, Lan J, Henshall DC, Chen D, O’Horo C, Simon RP, Chen J (2000a) Induction of oxidative DNA damage in the peri-infarct region after permanent focal cerebral ischemia. J Neurochem 75:1716–1728PubMedCrossRefGoogle Scholar
  135. Nagayama T, Simon RP, Chen D, Henshall DC, Pei W, Stetler RA, Chen J (2000b) Activation of poly(ADP-ribose) polymerase in the rat hippocampus may contribute to cellular recovery following sublethal transient global ischemia. J Neurochem 74:1636–1645PubMedCrossRefGoogle Scholar
  136. Najm IM, Hadam J, Ckakraverty D, Mikuni N, Penrod C, Sopa C, Markarian G, Luders HO, Babb T, Baudry M (1998) A short episode of seizure activity protects from status epilepticus-induced neuronal damage in rat brain. Brain Res 10(1–2):72–75CrossRefGoogle Scholar
  137. Nakamura K, Sakai W, Kawamoto T, Bree RT, Lowndes NF, Takeda S, Taniguchi Y (2006) Genetic dissection of vertebrate 53BP1: a major role in non-homologous end joining of DNA double strand breaks. DNA Repair (Amst) 5(6):741–749CrossRefGoogle Scholar
  138. Neema M, Navarro-Quiroga I, Chechlacz M, Gilliams-Francis K, Liu J, Lamonica K, Lin SL, Naegele JR (2005) DNA damage and nonhomologous end joining in excitotoxicity: neuroprotective role of DNA-PKcs in kainic acid-induced seizures. Hippocampus 15:1057–1071PubMedCrossRefGoogle Scholar
  139. Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA (2000) Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol Cell Biol 20:2996–3003PubMedCrossRefGoogle Scholar
  140. Nilsen H, Rosewell I, Robins P, Skjelbred CF, Andersen S, Slupphaug G, Daly G, Krokan HE, Lindahl T, Barnes DE (2000) Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication. Mol Cell 5:1059–1065PubMedCrossRefGoogle Scholar
  141. Norbury CJ, Zhivotovsky B (2004) DNA damage-induced apoptosis. Oncogene 23:2797–2808PubMedCrossRefGoogle Scholar
  142. Nouspikel T, Hanawalt PC (2000) Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol Cell Biol 20:1562–1570PubMedCrossRefGoogle Scholar
  143. Nouspikel T, Hanawalt PC (2002) DNA repair in terminally differentiated cells. DNA Repair (Amst) 1:59–75CrossRefGoogle Scholar
  144. Nowak E, Etienne O, Millet P, Lages CS, Mathieu C, Mouthon MA, Boussin FD (2006) Radiation-induced H2AX phosphorylation and neural precursor apoptosis in the developing brain of mice. Radiat Res 165:155–164PubMedCrossRefGoogle Scholar
  145. Onem G, Aral E, Enli Y, Oguz EO, Coskun E, Aybek H, Ozcan AV, Sacar M, Bir LS, Baltalarli A, Baycu C (2006) Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats. J Surg Res 131:124–130PubMedCrossRefGoogle Scholar
  146. Park EJ, Chan DW, Park JH, Oettinger MA, Kwon J (2003) DNA-PK is activated by nucleosomes and phosphorylates H2AX within the nucleosomes in an acetylation-dependent manner. Nucleic Acids Res 31:6819–6827PubMedCrossRefGoogle Scholar
  147. Patel MN (2002) Oxidative stress, mitochondrial dysfunction, and epilepsy. Free Radic Res 36:1139–1146PubMedCrossRefGoogle Scholar
  148. Patel M (2004) Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med 37:1951–1962PubMedCrossRefGoogle Scholar
  149. Patel M, Li QY (2003) Age dependence of seizure-induced oxidative stress. Neuroscience 118:431–437PubMedCrossRefGoogle Scholar
  150. Patel M, Li QY, Chang LY, Crapo J, Liang LP (2005) Activation of NADPH oxidase and extracellular superoxide production in seizure-induced hippocampal damage. J Neurochem 92:123–131PubMedCrossRefGoogle Scholar
  151. Phillis JW, Horrocks LA, Farooqui AA (2006) Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Brain Res Rev 52(2):201–243CrossRefGoogle Scholar
  152. Plamondon H, Blondeau N, Heurteaux C, Lazdunski M (1999) Mutually protective actions of kainic acid epileptic preconditioning and sublethal global ischemia on hippocampal neuronal death: involvement of adenosine A1 Receptors and KATP Channels. J Cereb Blood Flow Metab 19(12):1296–1308PubMedCrossRefGoogle Scholar
  153. Quach N, Chan T, Lu TA, Schreiber SS, Tan Z (2005) Induction of DNA repair proteins, Ref-1 and XRCC1, in adult rat brain following kainic acid-induced seizures. Brain Res 1042:236–240PubMedCrossRefGoogle Scholar
  154. Raji NS, Krishna TH, Rao KS (2002) DNA-polymerase alpha, beta, delta and epsilon activities in isolated neuronal and astroglial cell fractions from developing and aging rat cerebral cortex. Int J Dev Neurosci 20:491–496PubMedCrossRefGoogle Scholar
  155. Rao KS (2007) DNA repair in aging rat neurons. Neuroscience 145:1330–1340PubMedCrossRefGoogle Scholar
  156. Rao KS, Annapurna VV, Raji NS (2001) DNA polymerase-beta may be the main player for defective DNA repair in aging rat neurons. Ann N Y Acad Sci 928:113–120PubMedCrossRefGoogle Scholar
  157. Rapp A, Greulich KO (2004) After double-strand break induction by UV-A, homologous recombination and nonhomologous end joining cooperate at the same DSB if both systems are available. J Cell Sci 117:4935–4945PubMedCrossRefGoogle Scholar
  158. Rass U, Ahel I, West SC (2007) Defective DNA repair and neurodegenerative disease. Cell 130:991–1004PubMedCrossRefGoogle Scholar
  159. Ren K, de Ortiz SP (2002) Non-homologous DNA end joining in the mature rat brain. J Neurochem 80:949–959PubMedCrossRefGoogle Scholar
  160. Rolig RL, McKinnon PJ (2000) Linking DNA damage and neurodegeneration. Trends Neurosci 23:417–424PubMedCrossRefGoogle Scholar
  161. Rutten BP, Korr H, Steinbusch HW, Schmitz C (2003) The aging brain: less neurons could be better. Mech Ageing Dev 124:349–355PubMedCrossRefGoogle Scholar
  162. Sasahira M, Lowry T, Simon RP, Greenberg DA (1995) Epileptic tolerance: prior seizures protect against seizure-induced neuronal injury. Neurosci Lett 185:95–98PubMedCrossRefGoogle Scholar
  163. Satrustegui J, Richter C (1984) The role of hydroperoxides as calcium release agents in rat brain mitochondria. Arch Biochem Biophys 233:736–740PubMedCrossRefGoogle Scholar
  164. Sawada M, Sun W, Hayes P, Leskov K, Boothman DA, Matsuyama S (2003) Ku 70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 5:320–329PubMedCrossRefGoogle Scholar
  165. Schwob JE, Fuller T, Price JL, Olney JW (1980) Widespread patterns of neuronal damage following systemic or intracerebral injections of kainic acid: a histological study. Neuroscience 5:991–1014PubMedCrossRefGoogle Scholar
  166. Sekiguchi JM, Ferguson DO (2006) DNA double-strand break repair: a relentless hunt uncovers new prey. Cell 124:260–262PubMedCrossRefGoogle Scholar
  167. Shackelford DA (2006) DNA end joining activity is reduced in Alzheimer’s disease. Neurobiol Aging 27:596–605PubMedCrossRefGoogle Scholar
  168. Shackelford DA, Tobaru T, Zhang S, Zivin JA (1999) Changes in expression of the DNA repair protein complex DNA-dependent protein kinase after ischemia and reperfusion. J Neurosci 19:4727–4738PubMedGoogle Scholar
  169. Sharma S (2007) Age-related nonhomologous end joining activity in rat neurons. Brain Res Bull 73:48–54PubMedCrossRefGoogle Scholar
  170. Shin HJ, Lee JY, Son E, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS (2007) Curcumin attenuates the kainic acid-induced hippocampal cell death in the mice. Neurosci Lett 416:49–54PubMedCrossRefGoogle Scholar
  171. Simmet T, Seregi A, Hertting G (1987) Formation of sulphidopeptide-leukotrienes in brain tissue of spontaneously convulsing gerbils. Neuropharmacology 26:107–110PubMedCrossRefGoogle Scholar
  172. Simonian NA, Coyle JT (1996) Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol 36:83–106PubMedCrossRefGoogle Scholar
  173. Singleton BK, Jeggo PA (1999) Double-strand break repair and V(D)J recombination. In: Smith PJ, Christopher JJ (eds) DNA recombination and repair. Oxford University Press, Oxford, pp 16–37Google Scholar
  174. Sloviter RS, Dean E, Sollas AL, Goodman JH (1996) Apoptosis and necrosis induced in different hippocampal neuron populations by repetitive perforant path stimulation in the rat. J Comp Neurol 366:516–533PubMedCrossRefGoogle Scholar
  175. Slupphaug G, Kavli B, Krokan HE (2003) The interacting pathways for prevention and repair of oxidative DNA damage. Mutat. Res. 531:231–251PubMedGoogle Scholar
  176. Sperk G, Lassmann H, Baran H, Kish SJ, Seitelberger F, Hornykiewicz O (1983) Kainic acid induced seizures: neurochemical and histopathological changes. Neuroscience 10:1301–1315PubMedCrossRefGoogle Scholar
  177. Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (2003) MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421:961–966PubMedCrossRefGoogle Scholar
  178. Stiff T, O’Driscoll M, Rief N, Iwabuchi K, Lobrich M, Jeggo PA (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64:2390–2396PubMedCrossRefGoogle Scholar
  179. Stucki M, Jackson SP (2006) gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. DNA Repair (Amst) 5:534–543CrossRefGoogle Scholar
  180. Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP (2005) MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123:1213–1226PubMedCrossRefGoogle Scholar
  181. Sugawara T, Noshita N, Lewen A, Kim GW, Chan PH (2001) Neuronal expression of the DNA repair protein Ku 70 after ischemic preconditioning corresponds to tolerance to global cerebral ischemia. Stroke 32:2388–2393PubMedCrossRefGoogle Scholar
  182. Sumanont Y, Murakami Y, Tohda M, Vajragupta O, Watanabe H, Matsumoto K (2006) Prevention of kainic acid-induced changes in nitric oxide level and neuronal cell damage in the rat hippocampus by manganese complexes of curcumin and diacetylcurcumin. Life Sci 78:1884–1891PubMedCrossRefGoogle Scholar
  183. Sun FY, Lin X, Mao LZ, Ge WH, Zhang LM, Huang YL, Gu J (2002) Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. J Pineal Res 33:48–56PubMedCrossRefGoogle Scholar
  184. Tijsterman M, Verhage RA, Brouwer J (1999) Transcription-coupled and global genome repair in yeast and humans. In: Smith PJ, Jones CJ (eds) DNA recombination and repair. Oxford University Press, Oxford, pp 139–165Google Scholar
  185. Tretter L, dam-Vizi V (2005) Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci 360:2335–2345PubMedCrossRefGoogle Scholar
  186. Trujillo KM, Yuan SS, Lee EY, Sung P (1998) Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J Biol Chem 273:21447–21450PubMedCrossRefGoogle Scholar
  187. Tuunanen J, Lukasiuk K, Halonen T, Pitkanen A (1999) Status epilepticus-induced neuronal damage in the rat amygdaloid complex: distribution, time-course and mechanisms. Neuroscience 94:473–495PubMedCrossRefGoogle Scholar
  188. Ueda Y, Yokoyama H, Niwa R, Konaka R, Ohya-Nishiguchi H, Kamada H (1997) Generation of lipid radicals in the hippocampal extracellular space during kainic acid-induced seizures in rats. Epilepsy Res 26:329–333PubMedCrossRefGoogle Scholar
  189. Vemuri MC, Schiller E, Naegele JR (2001) Elevated DNA double strand breaks and apoptosis in the CNS of scid mutant mice. Cell Death Differ 8:245–255PubMedCrossRefGoogle Scholar
  190. Vogel R, Wiesinger H, Hamprecht B, Dringen R (1999) The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required. Neurosci Lett 275:97–100PubMedCrossRefGoogle Scholar
  191. Vyjayanti VN, Rao KS (2006) DNA double strand break repair in brain: reduced NHEJ activity in aging rat neurons. Neurosci Lett 393:18–22PubMedCrossRefGoogle Scholar
  192. Wang J, Markesbery WR, Lovell MA (2006) Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J Neurochem 96:825–832PubMedCrossRefGoogle Scholar
  193. West RB, Yaneva M, Lieber MR (1998) Productive and nonproductive complexes of Ku and DNA-dependent protein kinase at DNA termini. Mol Cell Biol 18:5908–5920PubMedGoogle Scholar
  194. Xia Z, Liu Y (2001) Reliable and global measurement of fluorescence resonance energy transfer using fluorescence microscopes. Biophys J 81:2395–2402PubMedCrossRefGoogle Scholar
  195. Yaneva M, Kowalewski T, Lieber MR (1997) Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studies. EMBO J 16:5098–5112PubMedCrossRefGoogle Scholar
  196. Zaleska MM, Wilson DF (1989) Lipid hydroperoxides inhibit reacylation of phospholipids in neuronal membranes. J Neurochem 52:255–260PubMedCrossRefGoogle Scholar
  197. Zhang WR, Hayashi T, Sasaki C, Sato K, Nagano I, Manabe Y, Abe K (2001) Attenuation of oxidative DNA damage with a novel antioxidant EPC-K1 in rat brain neuronal cells after transient middle cerebral artery occlusion. Neurol Res 23:676–680PubMedCrossRefGoogle Scholar
  198. Zhang X, Cui SS, Wallace AE, Hannesson DK, Schmued LC, Saucier DM, Honer WG, Corcoran ME (2002) Relations between brain pathology and temporal lobe epilepsy. J Neurosci 22:6052–6061PubMedGoogle Scholar
  199. Zhang B, Tanaka J, Yang L, Yang L, Sakanaka M, Hata R, Maeda N, Mitsuda N (2004) Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-1. Neuroscience 126:433–440PubMedCrossRefGoogle Scholar
  200. Zoccarato F, Cavallini L, Alexandre A (2004) Respiration-dependent removal of exogenous H2O2 in brain mitochondria: inhibition by Ca2+. J Biol Chem 279:4166–4174PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Departments of Pediatrics and PharmacologyGeorgetown UniversityWashingtonUSA
  2. 2.Interdisciplinary Program in Neuroscience and Department of PharmacologyGeorgetown UniversityGeorgetownUSA

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