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The Role of Free Radicals in the Nervous System

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Oxidative Stress and Free Radical Damage in Neurology

Abstract

This chapter is an introduction to the biology of reactive oxygen species (ROS) in the brain. In healthy aerobes, there is a balance between the production of various ROS and antioxidant defenses. Living organisms have not only adapted to coexistence with free radicals but have developed various mechanisms for the advantageous use of free radicals in various physiological functions. Infectious diseases were a powerful driver of natural selection in early human civilizations. Indeed, ROS participate directly in defense against infection. In a normal situation, microglia, which are resident macrophages of the brain, fight against infection by ROS. ROS are well recognized for playing a dual role, having both deleterious and beneficial effects, which in most cases depend on concentration. At high ROS concentrations there are harmful effects, and in a low–moderate concentration ROS are involved in physiological roles in cellular response to noxious stimuli. It was suggested that the main effects of ROS on cells are through their actions on signaling pathways rather than causing nonspecific damage. With aging, when these pathways deteriorate, accumulation of higher concentrations of ROS occurs in amounts beyond the capacity of antioxidants to cope. This deterioration results in the age-associated neurodegenerative disorders such as stroke and central nervous system (CNS) trauma as well as Parkinson’s and Alzheimer’s disease. Some of the CNS-evolved specific signaling pathways are described.

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References

  1. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine,. 4th edn. Oxford University Press, Oxford, 2007.

    Google Scholar 

  2. Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem.. 2006;97:1634–58.

    Article  CAS  PubMed  Google Scholar 

  3. Nohl H, Hegner D. Do mitochondria produce oxygen free radicals in vivo? Eur J Biochem. 1978;82:563–7.

    Article  CAS  PubMed  Google Scholar 

  4. Sohal RS. Mitochondria generate superoxide anion radicals and hydrogen peroxide. FASEB J. 1997;11:1269–70.

    CAS  PubMed  Google Scholar 

  5. Fridovich I. Superoxide dismutases. An adaptation to a paramagnetic gas. J Biol Chem. 1989;264:7761–4.

    CAS  PubMed  Google Scholar 

  6. Touati D. The molecular genetics of superoxide dismutase in E. coli. An approach to understanding the biological role and regulation of SOD in relation to other elements of the defense system against oxygen toxicity. Free Radic Biol Med. 1989;8:1–9.

    CAS  Google Scholar 

  7. Imlay JA, Chin SM, Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science. 1988;240:1302–9.

    Article  CAS  PubMed  Google Scholar 

  8. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1–85.

    Article  CAS  PubMed  Google Scholar 

  9. Yamazaki I, Piette LH. EPR spin trapping study on the oxidizing species formed in the reaction of the ferrous ion with hydrogen peroxide. J Am Chem Soc. 1991;113:7588–93.

    Article  CAS  Google Scholar 

  10. Jain A, Martensson J, Stole E, et al. Glutathione deficiency leads to mitochondrial damage in brain. Proc Natl Acad Sci USA. 1991;88:1913–7.

    Article  CAS  PubMed  Google Scholar 

  11. Cochrane CG. Mechanisms of oxidant injury of cells. Mol Aspects Med. 1991;12:137–47.

    Article  CAS  PubMed  Google Scholar 

  12. Halliwell B, Aruoma OI. DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett. 1991;28:9–19.

    Article  Google Scholar 

  13. Orrenius S, McConkey DJ, Bellomo G, et al. Role of Ca2+ in toxic cell killing. Trends Pharmacol Sci. 1989;10:281–5.

    Article  CAS  PubMed  Google Scholar 

  14. Asano T, Matsui T, Takuwa Y. Lipid peroxidation, protein kinase C and cerebral ischemia. Crit Rev Neurosurg. 1991;1:361–79.

    Google Scholar 

  15. Sevanian A, McLeod LL. Formation and biological reactivity of lipid peroxidation. In: Wallace KB, editors. Free radical toxicology. Washington, DC, Taylor & Francis, 1997:47–70.

    Google Scholar 

  16. Radi R, Beckman JS, Bush KM, et al. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem. 1991;266:4244–50.

    CAS  PubMed  Google Scholar 

  17. Beckman JS, Ischiropoulos H, Zhu L, et al. Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys. 1992;298:438–55.

    Article  CAS  PubMed  Google Scholar 

  18. Crow JP, Beckman NJS, McCord JM. Sensitivity of the zinc-thiolate moiety of yeast alcohol dehydrogenase to hypochlorite and perxoinitrite. Biochemistry. 1995;34:3544–52.

    Article  CAS  PubMed  Google Scholar 

  19. Radi R, Beckman JS, Bush KM, et al. Peroxynitrite induced membrane lipid peroxidation. The cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991;288:81–7.

    Google Scholar 

  20. Moreno JJ, Pryor WA. Inactivation of alpha 1-proteinase inhibitor by peroxynitrite. Chem Res Toxic. 1992;5:425–31.

    Article  CAS  Google Scholar 

  21. Kirkwood TB. Understanding the odd science of aging. Cell. 2005;120:437–47.

    Article  CAS  PubMed  Google Scholar 

  22. Maher P, Schubert D. Signaling by reactive oxygen species in the nervous system. Cell Mol Life Sci. 2000;57:1287–305.

    Article  CAS  PubMed  Google Scholar 

  23. Sugawara T, Fujimura M, Noshita N, et al. Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx. 2004;1:17–25.

    Article  PubMed  Google Scholar 

  24. Maher P. How protein kinase C activation protects nerve cells from oxidative stress-induced cell death. J Neurosci. 2001;21:2929–38.

    CAS  PubMed  Google Scholar 

  25. Kamada H, Nito C, Endo H, et al. Bad as a converging signaling molecule between survival PI3-K/Akt and death JNK in neurons after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2006;27:521–33.

    Article  PubMed  CAS  Google Scholar 

  26. Adibhatla RM, Hatcher JF, Dempsey RJ. Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem. 2002;80:12–23.

    Article  CAS  PubMed  Google Scholar 

  27. Saeed SA, Shad KF, Saleem T, et al. Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res. 2007;182:1–10.

    Article  PubMed  Google Scholar 

  28. Taylor JM, Crack PJ. Impact of oxidative stress on neuronal survival. Clin Exp Pharmacol Physiol. 2004;31:397–406.

    Article  CAS  PubMed  Google Scholar 

  29. Hewett SJ, Uliasz TF, Vidwans AS, et al. Cyclooxygenase-2 contributes to N-methyl-d-aspartate-mediated neuronal cell death in primary cortical cell culture. J Pharmacol Exp Ther. 2000;293:417–25.

    CAS  PubMed  Google Scholar 

  30. Toescu EC. Hypoxia sensing and pathways of cytosolic Ca2+ increases. Cell Calcium. 2004;36:187–99.

    Article  CAS  PubMed  Google Scholar 

  31. Chen RM, Chen TL, Chiu WT, et al. Molecular mechanism of nitric oxide-induced osteoblast apoptosis. J Orthop Res. 2005;23:462–8.

    Article  CAS  PubMed  Google Scholar 

  32. Maines MD. The heme oxygenase system: update. Antioxid Redox Signal. 2005;7:1761–6.

    Article  CAS  PubMed  Google Scholar 

  33. Poon HF, Calabrese V, Scapagnini G, et al. Free radicals: key to brain aging and heme oxygenase as a cellular response to oxidative stress. J Gerontol A Biol Sci Med Sci. 2004;59:478–93.

    PubMed  Google Scholar 

  34. Alam J, Cook JL. Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. Curr Pharm Des. 2003;9:2499–511.

    Article  CAS  PubMed  Google Scholar 

  35. Franklin TB, Krueger-Naug AM, Clarke DB, et al. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperthermia. 2005;21:379–92.

    Article  CAS  PubMed  Google Scholar 

  36. Igarashi K, Sun J. The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. Antioxid Redox Signal. 2006;8:107–18.

    Article  CAS  PubMed  Google Scholar 

  37. Calabrese V, Guagliano E, Sapienza M, et al. Redox regulation of cellular stress response in aging and neurodegenerative disorders: role of vitagenes. Neurochem Res. 2007;32:757–73.

    Article  CAS  PubMed  Google Scholar 

  38. Gilgun-Sherki Y, Rosenbaum Z, Melamed E et al. Antioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev. 2002;54:271–84.

    Article  CAS  PubMed  Google Scholar 

  39. Williams AJ, Berti R, Dave JR, et al. Delayed treatment of ischemia/reperfusion brain injury: Stroke. 2004;35:1186–91.

    Article  CAS  PubMed  Google Scholar 

  40. Van der Worp HB, Bar PR, Kappelle LJ, et al. Dietary vitamin E levels affect outcome of permanent focal cerebral ischemia in rats. Stroke. 1998;29:1002–5.

    CAS  PubMed  Google Scholar 

  41. Asai A, Tanahashi N, Qiu JH, et al. Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia. J Cereb Blood Flow Metab. 2002;22:705–10.

    Article  PubMed  Google Scholar 

  42. Bayir H, Marion DW, Puccio AM, et al. Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients. J Neurotrauma. 2004;21:1–8.

    Article  PubMed  Google Scholar 

  43. Ballabh P, Braun A, Nedergaard M. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16:1–13.

    Article  CAS  PubMed  Google Scholar 

  44. Phillis JW, O’Regan MH. A potentially critical role of phospholipases in central nervous system ischemic, traumatic, and neurodegenerative disorders. Brain Res Rev. 2004;44:13–47.

    Article  CAS  PubMed  Google Scholar 

  45. Liu D, Liu J, Sun D, et al. Spinal cord injury increases iron levels: catalytic production of hydroxyl radicals. Free Radic Biol Med. 2003;34:64–71.

    Article  CAS  PubMed  Google Scholar 

  46. Macdonald RL, Marton LS, Andrus PK, et al. Time course of production of hydroxyl free radical after subarachnoid hemorrhage in dogs. Life Sci. 2004;75:979–89.

    Article  CAS  PubMed  Google Scholar 

  47. Wagner KR, Sharp FR, Ardizzone TD, et al. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab. 2003;23:629–59.

    Article  CAS  PubMed  Google Scholar 

  48. Chang EF, Wong RJ, Vreman HJ, et al. Heme oxygenase-2 protects against lipid peroxidation-mediated cell loss and impaired motor recovery after traumatic brain injury. J Neurosci. 2003;23:3689–96.

    CAS  PubMed  Google Scholar 

  49. Berg D, Youdim MB, Riederer P. Redox imbalance. Cell Tissue Res. 2004;318:201–13.

    Article  PubMed  Google Scholar 

  50. Cui K, Luo X, Xu K, et al. Role of oxidative stress in neurodegeneration: recent developments in assay methods for oxidative stress and nutraceutical antioxidants. Prog Neuro-psychopharmacol Biol Psychiatry. 2004;28:771–99.

    Article  CAS  Google Scholar 

  51. Fato R, Bergamini C, Leoni S, et al. Generation of reactive oxygen species by mitochondrial complex I: implications in neurodegeneration. Neurochem Res. 2008;33:2487–501.

    Article  CAS  PubMed  Google Scholar 

  52. Uversky VN. Neurotoxicant-induced animal models of Parkinson’s disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell Tissue Res. 2004;318:225–41.

    Article  CAS  PubMed  Google Scholar 

  53. Bove J, Prou D, Perier C, et al. Toxin-induced models of Parkinson’s disease. NeuroRx. 2005;2:484–94.

    Article  PubMed  Google Scholar 

  54. Schober A. Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res. 2004;318:215–24.

    Article  PubMed  Google Scholar 

  55. Wersinger C, Sidhu A. An inflammatory pathomechanism for Parkinson’s disease? Curr Med Chem. 2006;13:591–602.

    Article  CAS  PubMed  Google Scholar 

  56. Landrigan PJ, Sonawane B, Butler RN, et al. Early environmental origins of neurodegenerative disease in later life. Environ Health Perspect. 2005;113:1230–3.

    Article  CAS  PubMed  Google Scholar 

  57. Maguire-Zeiss KA, Short DW, Federoff HJ. Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson’s disease? Brain Res Mol Brain Res. 2005;134:18–23.

    Article  CAS  PubMed  Google Scholar 

  58. Kotake Y, Ohta S. MPP+ analogs acting on mitochondria and inducing neuro-degeneration. Curr Med Chem. 2003;10:2507–16.

    Article  CAS  PubMed  Google Scholar 

  59. Shimizu K, Matsubara K, Ohtaki K, et al. Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture. Neurosci Res. 2003;46:523–32.

    Article  CAS  PubMed  Google Scholar 

  60. Peng J, Stevenson FF, Doctrow SR, et al. Superoxide dismutase/catalase mimetics are neuroprotective against selective paraquat-mediated dopaminergic neuron death in the substantial nigra: implications for Parkinson disease. J Biol Chem. 2005;280:2194–8.

    Google Scholar 

  61. Yang W, Tiffany-Castiglioni E. The bipyridyl herbicide paraquat produces oxidative stress-mediated toxicity in human neuroblastoma SH-SY5Y cells: relevance to the dopaminergic pathogenesis. J Toxicol Environ Health Part A. 2005;68:1939–61.

    Article  CAS  PubMed  Google Scholar 

  62. Thiruchelvam M, Prokopenko O, Cory-Slechta DA, et al. Overexpression of superoxide dismutase or glutathione peroxidase protects against the paraquat + maneb-induced Parkinson disease phenotype. J Biol Chem. 2005;280:22530–9.

    Article  CAS  PubMed  Google Scholar 

  63. Shimizu K, Matsubara K, Ohtaki K, et al. Paraquat induces long-lasting dopamine overflow through the excitotoxic pathway in the striatum of freely moving rats. Brain Res. 2003;976:243–52.

    Article  CAS  PubMed  Google Scholar 

  64. Bretaud S, Lee S, Guo S. Sensitivity of zebrafish to environmental toxins implicated in Parkinson’s disease. Neurotoxicol Teratol. 2004;26:857–64.

    Article  CAS  PubMed  Google Scholar 

  65. Chun HS, Gibson GE, DeGiorgio LA, et al. Dopaminergic cell death induced by MPP (+), oxidant and specific neurotoxicants shares the common molecular mechanism. J Neurochem. 2001;76:1010–21.

    Article  CAS  PubMed  Google Scholar 

  66. Block ML, Li G, Qin L, et al. Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin. FASEB J. 2006;20:251–8.

    Article  CAS  PubMed  Google Scholar 

  67. Li J, Baud O, Vartanian T, et al. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA. 2005;102:9936–41.

    Article  CAS  PubMed  Google Scholar 

  68. Zhang W, Wang T, Pei Z, et al. aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 2005;19:533–42.

    Article  CAS  PubMed  Google Scholar 

  69. Dringen R. Oxidative and antioxidative potential of brain microglial cells. Antioxid Redox Signal. 2005;7:1223–33.

    Article  CAS  PubMed  Google Scholar 

  70. Scheller C, Sopper S, Jenuwein M, et al. Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation. J Neurochem. 2005;95:377–87.

    Article  CAS  PubMed  Google Scholar 

  71. Gao HM, Hong JS, Zhang W, et al. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci. 2002;22:782–90.

    CAS  PubMed  Google Scholar 

  72. Casarejos MJ, Menendez J, Solano RM, et al. Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. J Neurochem. 2006;97:934–46.

    Article  CAS  PubMed  Google Scholar 

  73. Croisier E, Moran LB, Dexter DT, et al. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation. 2005;2:14–22.

    Article  PubMed  CAS  Google Scholar 

  74. Miller RL, James-Kracke M, Sun GY, et al. Oxidative and inflammatory pathways in Parkinson’s disease. Neurochem Res. 2009;34:55–65.

    Article  CAS  PubMed  Google Scholar 

  75. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med. 1997;23:134–47.

    Article  CAS  PubMed  Google Scholar 

  76. Zhu X, Smith MA, Perry G, et al. Mitochondrial failures in Alzheimer’s disease. Am J Alzheimer’s Dis Other Demen. 2004;19:345–52.

    Article  Google Scholar 

  77. Block ML. NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci. 2008;9:S8.

    Article  PubMed  CAS  Google Scholar 

  78. Friedlich AL, Butcher LL. Involvement of free oxygen radicals in beta-amyloidosis: an hypothesis. Neurobiol Aging. 1994;15:443–55.

    Article  CAS  PubMed  Google Scholar 

  79. Hashimoto M, Rockenstein E, Crews L, et al. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med. 2003;4:21–36.

    Article  CAS  PubMed  Google Scholar 

  80. Dyrks T, Dyrks E, Hartmann T, et al. Amyloidogenicity of beta A4 and beta A4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem. 1992;267:18210–7.

    CAS  PubMed  Google Scholar 

  81. Hensley K, Carney J, Hall N, et al. Electron paramagnetic resonance investigations of free radical-induced alterations in neocortical synaptosomal membrane protein infrastructure. Free Radic Biol Med. 1994;17:321–31.

    Article  CAS  PubMed  Google Scholar 

  82. Behl C, Davis JB, Lesley R, et al. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994;77:817–27.

    Article  CAS  PubMed  Google Scholar 

  83. Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Disc. 2004;3:205–14.

    Article  CAS  Google Scholar 

  84. Abramov AY, Canevari L, Duchen MR. Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci. 2004;24:565–75.

    Article  CAS  PubMed  Google Scholar 

  85. Pappolla MA, Sos M, Omar RA, et al. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci. 1997;17:1683–90.

    CAS  PubMed  Google Scholar 

  86. Reiter RJ. The ageing pineal gland and its physiological consequences. Bio Essays. 1992;14:169–75.

    CAS  Google Scholar 

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  1. Life Science Laboratory, Weizmann Science Park, Ness-Ziona, Israel

    Joseph Friedman

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Correspondence to Joseph Friedman .

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  1. Medical School, Dept. Neurology, Tel Aviv University, Tel Aviv, 69978, Israel

    Natan Gadoth

  2. Neurochirurgische Klinik, Abt. Neuropathologie, Universitätsklinikum Mainz, Langenbeckstr. 1, Mainz, 55131, Germany

    Hans Hilmar Göbel

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Friedman, J. (2011). The Role of Free Radicals in the Nervous System. In: Gadoth, N., Göbel, H. (eds) Oxidative Stress and Free Radical Damage in Neurology. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-60327-514-9_1

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