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. 2006 Apr 5;15(3):225–233. doi: 10.1111/j.1750-3639.2005.tb00525.x

Oxidative and Nitrative Injury in Periventricular Leukomalacia: A Review

R L Haynes 1,5,✉, O Baud 2,5, J Li 3, H C Kinney 1, J J Volpe 3, R D Folkerth 1,4
PMCID: PMC8095889  PMID: 16196389

Abstract

Periventricular leukomalacia (PVL) is the major substrate of cerebral palsy in survivors of prematurity. Its pathogenesis is complex and likely involves ischemia/reperfusion in the critically ill premature infant, with impaired regulation of cerebral blood flow, as well as inflammatory mechanisms associated with maternal and/or fetal infection. During the peak period of vulnerability for PVL, developing oligodendrocytes (OLs) predominate in the white matter. We hypothesize that free radical injury to the developing OLs underlies, in part, the pathogenesis of PVL and the hypomyelination seen in long‐term survivors. In human PVL, free radical injury is supported by evidence of oxidative and nitrative stress with markers to lipid peroxidation and nitrotyrosine, respectively. Evidence in normal human cerebral white matter suggests an underlying vulnerability of the premature infant to free radical injury resulting from a developmental mismatch of antioxidant enzymes (AOE) and subsequent imbalance in oxidant metabolism. In vitro studies using rodent OLs suggest that maturational susceptibility to reactive oxygen species is dependent, not only on levels of individual AOE, but also on specific interactions between these enzymes. Rodent in vitro data further suggest 2 mechanisms of nitric oxide damage: one involving the direct effect of nitric oxide on OL mitochondrial integrity and function, and the other involving an activation of microglia and subsequent release of reactive nitrogen species. The latter mechanism, while important in rodent studies, remains to be determined in the pathogenesis of human PVL. These observations together expand our knowledge of the role that free radical injury plays in the pathogenesis of PVL, and may contribute to the eventual development of therapeutic strategies to alleviate the burden of oxidative and nitrative injury in the premature infant at risk for PVL.

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References

  • 1. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32:1–14. [PubMed] [Google Scholar]
  • 2. Back SA, Gan X, Li Y, Rosenberg PR, Volpe JJ (1998) Maturation‐dependent vulnerability of oligodendrocytes to oxidative stress‐induced death caused by glutathione depletion. J Neurosci 18:6241–6253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Back SA, Luo NL, Borenstein NS, Levine JM, Volpe JJ, Kinney HC (2001) Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 21:1302–1312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Banks WA, Kastin AJ, Gutierrez EG (1993) Interleukin‐1 alpha in blood has direct access to cortical brain cells. Neurosci Lett 163:41–44. [DOI] [PubMed] [Google Scholar]
  • 5. Banks WA, Kastin AJ, Gutierrez EG (1994) Penetration of interleukin‐6 across the murine blood‐brain barrier. Neurosci Lett 179:53–56. [DOI] [PubMed] [Google Scholar]
  • 6. Banks WA, Ortiz L, Plotkin SR, Kastin AJ (1991) Human interleukin (IL) 1 alpha, murine IL‐1 alpha and murine IL‐1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J Pharmacol Exp Ther 259:988–996. [PubMed] [Google Scholar]
  • 7. Barbeito LH, Pehar M, Cassina P, Vargas MR, Peluffo H, Viera L, Estevez AG, Beckman JS (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Rev 47:263–274. [DOI] [PubMed] [Google Scholar]
  • 8. Bartnik BL, Juurlink BH, Devon RM (2000) Macrophages: their myelinotrophic or neurotoxic actions depend upon tissue oxidative stress. Mult Scler 6:37–42. [DOI] [PubMed] [Google Scholar]
  • 9. Baud O, Greene AE, Li J, Wang H, Volpe JJ, Rosenberg PA (2004) Glutathione peroxidasecatalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes. J Neurosci 24:1531–1540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Baud O, Haynes RF, Wang H, Folkerth RD, Li J, Volpe JJ, Rosenberg PA (2004) Developmental up‐regulation of MnSOD in rat oligodendrocytes confers protection against oxidative injury. Eur J Neurosci 20:29–40. [DOI] [PubMed] [Google Scholar]
  • 11. Baud O, Li J, Zhang Y, Neve RL, Volpe JJ, Rosenberg PA (2004) Nitric oxide‐induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis‐inducing factor translocation. Eur J Neurosci 20:1713–1726. [DOI] [PubMed] [Google Scholar]
  • 12. Bolanos JP, Almeida A (1999) Roles of nitric oxide in brain hypoxia‐ischemia. Biochim Biophys Acta 1411:415–436. [DOI] [PubMed] [Google Scholar]
  • 13. Boullerne AI, Nedelkoska L, Benjamins JA (2001) Role of calcium in nitric oxide‐induced cytotoxicity: EGTA protects mouse oligodendrocytes. J Neurosci Res 63:124–135. [DOI] [PubMed] [Google Scholar]
  • 14. Brett FM, Mizisin AP, Powell HC, Campbell IL (1995) Evolution of neuropathologic abnormalities associated with blood‐brain barrier breakdown in transgenic mice expressing interleukin‐6 in astrocytes. J Neuropathol Exp Neurol 54:766–775. [DOI] [PubMed] [Google Scholar]
  • 15. Chan PH (1994) Oxygen radicals in focal cerebral ischemia. Brain Pathol 4:59–65. [DOI] [PubMed] [Google Scholar]
  • 16. Choi JJ, Kim WK (1998) Potentiated glucose deprivation‐induced death of astrocytes after induction of iNOS . J Neurosci Res 54:870–875. [DOI] [PubMed] [Google Scholar]
  • 17. Colasanti M, Persichini T, Di Pucchio T, Gremo F, Lauro GM (1995) Human ramified microglial cells produce nitric oxide upon Escherichia coli lipopolysaccharide and tumor necrosis factor alpha stimulation. Neurosci Lett 200:144–146. [DOI] [PubMed] [Google Scholar]
  • 18. Colasanti M, Persichini T, Menegazzi M, Mariotto S, Giordano E, Caldarera CM, Sogos V, Lauro GM, Suzuki H (1995) Induction of nitric oxide synthase mRNA expression. Suppression by exogenous nitric oxide. J Biol Chem 270:26731–26733. [DOI] [PubMed] [Google Scholar]
  • 19. Cotran R, Kumar V, Collins T (1999) Robbins Pathologic Basis of Disease. (eds). WB Saunders Company: Philadelphia . pp. 1–30. [Google Scholar]
  • 20. Deguchi K, Mizuguchi M, Takashima S (1996) Immunohistochemical expression of tumor necrosis factor a in neonatal leukomalacia. Pediatr Neurol 14:13–16. [DOI] [PubMed] [Google Scholar]
  • 21. Denicola A, Souza JM, Radi R (1998) Diffusion of peroxynitrite across erythrocyte membranes. Proc Natl Acad Sci U S A 95:3566–3571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. DeSilva TM, Kinney HC, Volpe JJ, Rosenberg PA (2002) Glutamate transporter expression in cerebral white matter of the developing human brain. Abstract Viewer/Itinerary Planner, Washington , DC : Society for Neuroscience (online):Program No. 44.48. [Google Scholar]
  • 23. Ding M, Pierre BA St, Parkinson JF, Medberry P, Wong JL, Rogers NE, Ignarro LJ, Merrill JE (1997) Inducible nitric‐oxide synthase and nitric oxide production in human fetal astrocytes and microglia. A kinetic analysis. J Biol Chem 272:11327–11335. [DOI] [PubMed] [Google Scholar]
  • 24. Fellman V, Raivio KO (1997) Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 41:599–606. [DOI] [PubMed] [Google Scholar]
  • 25. Ferriero DM (2001) Oxidant mechanisms in neonatal hypoxia‐ischemia. Dev Neurosci 23:198–202. [DOI] [PubMed] [Google Scholar]
  • 26. Folkerth RD, Haynes RL, Borenstein NS, Belliveau RA, Trachtenberg F, Rosenberg PA, Volpe JJ, Kinney HC (2004) Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J Neuropathol Exp Neurol 63:990–999. [DOI] [PubMed] [Google Scholar]
  • 27. Folkerth RD, Keefe RJ, Haynes RL, Trachtenberg FL, Volpe JJ, Kinney HC (2004) Interferongamma expression in periventricular leukomalacia in the human brain. Brain Pathol 14:265–274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Follett PL, Rosenberg PA, Volpe JJ, Jensen FE (2000) NBQX attenuates excitotoxic injury in developing white matter. J Neurosci 20:9235–9241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Garthwaite G, Goodwin DA, Batchelor AM, Leeming K, Garthwaite J (2002) Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience 109:145–155. [DOI] [PubMed] [Google Scholar]
  • 30. Gutierrez EG, Banks WA, Kastin AJ (1993) Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 47:169–176. [DOI] [PubMed] [Google Scholar]
  • 31. Haynes RL, Folkerth RD, Keefe RJ, Sung I, Swzeda LI, Rosenberg PA, Volpe JJ, Kinney HC (2003) Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropathol Exp Neurol 62:441–450. [DOI] [PubMed] [Google Scholar]
  • 32. Heneka MT, Wiesinger H, Dumitrescu‐Ozimek L, Riederer P, Feinstein DL, Klockgether T (2001) Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol 60:906–916. [DOI] [PubMed] [Google Scholar]
  • 33. Hill KE, Zollinger LV, Watt HE, Carlson NG, Rose JW (2004) Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol 151:171–179. [DOI] [PubMed] [Google Scholar]
  • 34. Hoyert DL, Freedman MA, Strobino DM, Guyer B (2001) Annual summary of vital statistics: 2000. Pediatrics 108:1241–1255. [DOI] [PubMed] [Google Scholar]
  • 35. Itoh T, Beesley J, Itoh A, Cohen AS, Kavanaugh B, Coulter DA, Grinspan JB, Pleasure D (2002) AMPA glutamate receptor‐mediated calcium signaling is transiently enhanced during development of oligodendrocytes. J Neurochem 81:390–402. [DOI] [PubMed] [Google Scholar]
  • 36. Janabi N (2002) Selective inhibition of cyclooxygenase‐2 expression by 15‐deoxy‐Del‐ta(12,14)(12,14)‐prostaglandin J(2) in activated human astrocytes, but not in human brain macrophages. J Immunol 168:4747–4755. [DOI] [PubMed] [Google Scholar]
  • 37. Janabi N, Chabrier S, Tardieu M (1996) Endogenous nitric oxide activates prostaglandin F2 alpha production in human microglial cells but not in astrocytes: a study of interactions between eicosanoids, nitric oxide, and superoxide anion (O2‐) regulatory pathways. J Immunol 157:2129–2135. [PubMed] [Google Scholar]
  • 38. Kadhim H, Tabarki B, de Prez C, Rona AM, Sebire G (2002) Interleukin‐2 in the pathogenesis of perinatal white matter damage. Neurology 58:1125–1128. [DOI] [PubMed] [Google Scholar]
  • 39. Kadhim H, Tabarki B, de Prez C, Sebire G (2003) Cytokine immunoreactivity in cortical and subcortical neurons in periventricular leukomalacia: are cytokines implicated in neuronal dysfunction in cerebral palsy Acta Neuropathol (Berl) 105:209–216. [DOI] [PubMed] [Google Scholar]
  • 40. Kadhim HJ, Tabarki B, Verellen G, de Prez C, Rona A‐M, Sebire G (2001) Inflammatory cytokines in the pathogenesis of periventricular leukomalacia. Neurology 56:1278–1284. [DOI] [PubMed] [Google Scholar]
  • 41. Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in Parkinson's disease: iNOS, lipocortin‐1, and cyclooxygenases‐1 and ‐2. Mol Cell Neurosci 16:724–739. [DOI] [PubMed] [Google Scholar]
  • 42. Kong GY, Peng ZC, Costanzo C, Kristensson K, Bentivoglio M (2000) Inducible nitric oxide synthase expression elicited in the mouse brain by inflammatory mediators circulating in the cerebrospinal fluid. Brain Res 878:105–118. [DOI] [PubMed] [Google Scholar]
  • 43. Lee JC, Cho GS, Kim HJ, Lim JH, Oh YK, Nam W, Chung JH, Kim WK (2005) Accelerated cerebral ischemic injury by activated macrophages/microglia after lipopolysaccharide microinjection into rat corpus callosum. Glia 50:168–181. [DOI] [PubMed] [Google Scholar]
  • 44. Lee SC, Dickson DW, Liu W, Brosnan CF (1993) Induction of nitric oxide synthase activity in human astrocytes by interleukin‐1 beta and interferon‐gamma. J Neuroimmunol 46:19–24. [DOI] [PubMed] [Google Scholar]
  • 45. Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T (2002) The toll‐like receptor TLR4 is necessary for lipopolysaccharide‐induced oligodendrocyte injury in the CNS. J Neurosci 22:2478–2486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Lerouet D, Beray‐Berthat V, Palmier B, Plotkine M, Margaill I (2002) Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res 958:166–175. [DOI] [PubMed] [Google Scholar]
  • 47. Li J, Baud O, Vartanian T, Volpe J, Rosenberg P (2005) Lipopolysaccharide‐activated microglia mediate death of developing oligodendrocytes by generating peroxynitrite via inducible nitric oxide synthase and NADPH oxidase. PNAS 102:9936–9941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Liu JS, Zhao ML, Brosnan CF, Lee SC (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 158:2057–2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Loeffler DA, LeWitt PA, Juneau PL, Sima AA, Nguyen HU, DeMaggio AJ, Brickman CM, Brewer GJ, Dick RD, Troyer MD, et al (1996) Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res 738:265–274. [DOI] [PubMed] [Google Scholar]
  • 50. Lynch RE, Fridovich I (1978) Permeation of the erythrocyte stroma by superoxide radical. J Biol Chem 253:4697–4699. [PubMed] [Google Scholar]
  • 51. Maalouf EF, Duggan PJ, Counsell S, Rutherford MA, Cowan F, Azzopardi D, Edwards AD (2001) Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants. Pediatrics 107:719–727. [DOI] [PubMed] [Google Scholar]
  • 52. Mackenzie‐Graham AJ, Mitrovic B, Smoll A, Merrill JE (1994) Differential sensitivity to nitric oxide in immortalized, cloned murine oligodendrocyte cell lines. Dev Neurosci 16:162–171. [DOI] [PubMed] [Google Scholar]
  • 53. McDonald JW, Levine JM, Qu Y (1998) Multiple classes of the oligodendrocyte lineage are highly vulnerable to excitotoxicity. Neuroreport 9:2757–2762. [DOI] [PubMed] [Google Scholar]
  • 54. Merrill JE, Ignarro LJ, Sherman MP, Melinek J, Lane TE (1993) Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol 151:2132–2141. [PubMed] [Google Scholar]
  • 55. Mitrovic B, Ignarro LJ, Vinters HV, Akers MA, Schmid I, Uittenbogaart C, Merrill JE (1995) Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience 65:531–539. [DOI] [PubMed] [Google Scholar]
  • 56. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765. [DOI] [PubMed] [Google Scholar]
  • 57. Pachter JS, de Vries HE, Fabry Z (2003) The blood‐brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62:593–604. [DOI] [PubMed] [Google Scholar]
  • 58. Park SY, Lee H, Hur J, Kim SY, Kim H, Park JH, Cha S, Kang SS, Cho GJ, Choi WS, et al (2002) Hypoxia induces nitric oxide production in mouse microglia via p38 mitogen‐activated protein kinase pathway. Mol Brain Res 107:9–16. [DOI] [PubMed] [Google Scholar]
  • 59. Plesnila N (2004) Role of mitochondrial proteins for neuronal cell death after focal cerebral ischemia. Acta Neurochir Suppl 89:15–19. [DOI] [PubMed] [Google Scholar]
  • 60. Poli G, Leonarduzzi G, Biasi F, Chiarpotto E (2004) Oxidative stress and cell signalling. Curr Med Chem 11:1163–1182. [DOI] [PubMed] [Google Scholar]
  • 61. Possel H, Noack H, Putzke J, Wolf G, Sies H (2000) Selective upregulation of inducible nitric oxide synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies. Glia 32:51–59. [DOI] [PubMed] [Google Scholar]
  • 62. Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong JS (2002) Microglia enhance beta‐amyloid peptideinduced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem 83:973–983. [DOI] [PubMed] [Google Scholar]
  • 63. Reynolds IJ, Hastings TG (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci 15:3318–3327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Rezaie P, Dean A (2002) Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology 22:106–132. [DOI] [PubMed] [Google Scholar]
  • 65. Rivest S (2003) Molecular insights on the cerebral innate immune system. Brain Behav Immun 17:13–19. [DOI] [PubMed] [Google Scholar]
  • 66. Rodrigo J, Alonso D, Fernandez AP, Serrano J, Richart A, Lopez JC, Santacana M, Martinez‐Murillo R, Bentura ML, Ghiglione M, et al (2001) Neuronal and inducible nitric oxide synthase expression and protein nitration in rat cerebellum after oxygen and glucose deprivation. Brain Res 909:20–45. [DOI] [PubMed] [Google Scholar]
  • 67. Rosin C, Bates TE, Skaper SD (2004) Excitatory amino acid induced oligodendrocyte cell death in vitro: receptor‐dependent and ‐independent mechanisms. J Neurochem 90:1173–1185. [DOI] [PubMed] [Google Scholar]
  • 68. Saija A, Princi P, Lanza M, Scalese M, Aramnejad E, de Sarro A (1995) Systemic cytokine administration can affect blood‐brain barrier permeability in the rat. Life Sci 56:775–784. [DOI] [PubMed] [Google Scholar]
  • 69. Sasaki S, Shibata N, Komori T, Iwata M (2000) iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. Neurosci Lett 291:44–48. [DOI] [PubMed] [Google Scholar]
  • 70. Sauer H, Wefer K, Vetrugno V, Pocchiari M, Gissel C, Sachinidis A, Hescheler J, Wartenberg M (2003) Regulation of intrinsic prion protein by growth factors and TNF‐alpha: the role of intracellular reactive oxygen species. Free Radic Biol Med 35:586–594. [DOI] [PubMed] [Google Scholar]
  • 71. Scott GS, Virag L, Szabo C, Hooper DC (2003) Peroxynitrite‐induced oligodendrocyte toxicity is not dependent on poly (ADP‐ribose) polymerase activation. Glia 41:105–116. [DOI] [PubMed] [Google Scholar]
  • 72. Shimohama S, Tanino H, Kawakami N, Okamura N, Kodama H, Yamaguchi T, Hayakawa T, Nunomura A, Chiba S, Perry G, et al (2000) Activation of NADPH oxidase in Alzheimer's disease brains. Biochem Biophys Res Commun 273:5–9. [DOI] [PubMed] [Google Scholar]
  • 73. Shiva S, Moellering D, Ramachandran A, Levonen AL, Landar A, Venkatraman A, Ceaser E, Ulasova E, Crawford JH, Brookes PS, et al (2004) Redox signalling: from nitric oxide to oxidized lipids. Biochem Soc Symp 71:107–120. [DOI] [PubMed] [Google Scholar]
  • 74. Siushansian R, Wilson JX (1995) Ascorbate transport and intracellular concentration in cerebral astrocytes. J Neurochem 65:41–49. [DOI] [PubMed] [Google Scholar]
  • 75. Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1:232–241. [DOI] [PubMed] [Google Scholar]
  • 76. Sola C, Casal C, Tusell JM, Serratosa J (2002) Astrocytes enhance lipopolysaccharide‐induced nitric oxide production by microglial cells. Eur J Neurosci 16:1275–1283. [DOI] [PubMed] [Google Scholar]
  • 77. Talos DM, Follett P, Levada RE, Volpe JJ, Jensen FE (2004) AMPA receptor subunit expression in the fetal human brain at midgestation. Abstract Viewer/Itinerary Planner, Washington , DC : Society for Neuroscience (online): Program No. 99.99. [Google Scholar]
  • 78. Togo T, Katsuse O, Iseki E (2004) Nitric oxide pathways in Alzheimer's disease and other neurodegenerative dementias. Neurol Res 26:563–566. [DOI] [PubMed] [Google Scholar]
  • 79. Trembovler V, Beit‐Yannai E, Younis F, Gallily R, Horowitz M, Shohami E (1999) Antioxidants attenuate acute toxicity of tumor necrosis factor‐alpha induced by brain injury in rat. J Interferon Cytokine Res 19:791–795. [DOI] [PubMed] [Google Scholar]
  • 80. Volpe JJ (2003) Cerebral white matter injury of the premature infant‐more common than you think. Pediatrics 112:176–180. [DOI] [PubMed] [Google Scholar]
  • 81. Wang H, Li J, Follett PL, Zhang Y, Cotanche DA, Jensen FE, Volpe JJ, Rosenberg PA (2004) 12‐Li‐poxygenase plays a key role in cell death caused by glutathione depletion and arachidonic acid in rat oligodendrocytes. Eur J Neurosci 20:2049–2058. [DOI] [PubMed] [Google Scholar]
  • 82. Wilde GJ, Pringle AK, Sundstrom LE, Mann DA, Iannotti F (2000) Attenuation and augmentation of ischaemia‐related neuronal death by tumour necrosis factor‐alpha in vitro. Eur J Neurosci 12:3863–3870. [DOI] [PubMed] [Google Scholar]
  • 83. Wong A, Luth HJ, Deuther‐Conrad W, DukicStefanovic S, Gasic‐Milenkovic J, Arendt T, Munch G (2001) Advanced glycation endproducts colocalize with inducible nitric oxide synthase in Alzheimer's disease. Brain Res 920:32–40. [DOI] [PubMed] [Google Scholar]
  • 84. Wright JL, Merchant RE (1994) Blood‐brain barrier changes following intracerebral injection of human recombinant tumor necrosis factor‐alpha in the rat. J Neurooncol 20:17–25. [DOI] [PubMed] [Google Scholar]
  • 85. Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD (2002) Peroxynitrite mediates neurotoxicity of amyloid b‐peptide 1–42‐ and lipopolysaccharide‐activated microglia. J Neurosci 22:3484–3492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Yoon BH, Romero R, Kim CJ, Koo JN, Choe G, Syn HC, Chi JG (1997) High expression of tumor necrosis factor‐alpha and interleukin‐6 in periventricular leukomalacia. Am J Obstet Gynecol 177:406–411. [DOI] [PubMed] [Google Scholar]
  • 87. Yoshida T, Tanaka M, Sotomatsu A, Hirai S (1995) Activated microglia cause superoxide‐mediated release of iron from ferritin. Neurosci Lett 190:21–24. [DOI] [PubMed] [Google Scholar]
  • 88. Zhao ML, Liu JS, He D, Dickson DW, Lee SC (1998) Inducible nitric oxide synthase expression is selectively induced in astrocytes isolated from adult human brain. Brain Res 813:402–405. [DOI] [PubMed] [Google Scholar]
  • 89. Zhu DY, Deng Q, Yao HH, Wang DC, Deng Y, Liu GQ (2002) Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice. Life Sci 71:1985–1996. [DOI] [PubMed] [Google Scholar]
  • 90. Zhu DY, Liu SH, Sun HS, Lu YM (2003) Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 23:223–229. [DOI] [PMC free article] [PubMed] [Google Scholar]

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