Immune Cell-Derived Free Radicals in Acute Brain Injury

  • Purnima Narasimhan
  • Hiroyuki Sakata
  • Joo Eun Jung
  • Tatsuro Nishi
  • Takuma Wakai
  • Carolina M. Maier
  • Pak H. Chan
Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR, volume 6)

Abstract

Oxidative stress, which generates reactive oxygen species (ROS), plays an important role after acute brain injuries, including transient cerebral ischemia. Brain injuries like ischemic–reperfusion result in a surge of excess oxygen that leads to generation of free radicals. Free radicals are present at low levels in the normal state where they play a critical role in signaling pathways. Antioxidants help in maintaining the redox level in the cells, but during an insult this homeostasis is disturbed resulting in excessive ROS. Mitochondrial ROS are among the main intracellular ROS. Cerebral ischemia triggers inflammation in response to injury, which also leads to the generation of free radicals and eventually to neuronal cell death. Studies using genetically manipulated animals where antioxidant genes are overexpressed or knocked down show the key role that ROS play in ischemia. Oxidative stress affects the injured area in a multifaceted way. It activates apoptotic markers, inflammatory mediators including cytokines and chemokines, and transcriptional activators. Therefore, it has a significant function in cell death and survival signaling cascades. Several recent reports have demonstrated the various effects of ROS generation and its link to the inflammatory response after ischemia. In this chapter, we present an overview of these mechanisms that have been elucidated, focusing on the damaging effects of ROS and their crucial role in inflammation after stroke.

Keywords

Zinc H2O2 Ischemia Hydroxyl Attenuation 

Abbreviations

cyt c

Cytochrome c

DAPI

4′,6 Diamidino-2-phenylindole

GPx

Glutathione peroxidase

HEt

Hydroethidine

HO-1

Hemoxygenase-1

ICAM1

Intercellular adhesion molecule 1

IL

Interleukin

I/R

Ischemia/reperfusion

MCAO

Middle cerebral artery occlusion

MCP-1

Monocyte chemoattractant protein-1

MIP-1α

Macrophage inflammatory protein-1α

mNSS

Modified neurologic severity scores

NF-κB

Nuclear factor-kappa B

nNOS

Neuronal nitric oxide synthase

NO

Nitric oxide

non-PC

Non-preconditioned

NOX

NADPH oxidase

NQO1

NADH quinone oxidoreductase

NSCs

Neural stem cells

O2ˉ

Superoxide anion

O.D.

Optical density

OH

Hydroxyl ion

ONOO

Peroxynitrite

PC

Preconditioned

ROS

Reactive oxygen species

s.d.

Standard deviation

siRNA

Small interfering RNA

SOD

Superoxide dismutase

STAT3

Signal transducer and activator of transcription 3

Tg

Transgenic

TNF-α

Tumor necrosis factor-α

TUNEL

Terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling

Wt

Wild-type

Notes

Acknowledgments

This work was supported by NIH grants PO1 NS014543, RO1 NS025372, and RO1 NS038653, and by the James R. Doty Endowment.

References

  1. 1.
    Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734–44PubMedCrossRefGoogle Scholar
  2. 2.
    Barone FC, Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819–34PubMedCrossRefGoogle Scholar
  3. 3.
    Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR (1995) Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 37:800–5PubMedCrossRefGoogle Scholar
  4. 4.
    Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313PubMedCrossRefGoogle Scholar
  5. 5.
    Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE et al (2010) Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 30:1306–17PubMedCrossRefGoogle Scholar
  6. 6.
    Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H et al (2009) NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12:857–63PubMedCrossRefGoogle Scholar
  7. 7.
    Brivanlou AH, Darnell JE Jr (2002) Signal transduction and the control of gene expression. Science 295:813–8PubMedCrossRefGoogle Scholar
  8. 8.
    Carvalho-Tavares J, Hickey MJ, Hutchison J, Michaud J, Sutcliffe IT, Kubes P (2000) A role for platelets and endothelial selectins in tumor necrosis factor-α–induced leukocyte recruitment in the brain microvasculature. Circ Res 87:1141–8PubMedCrossRefGoogle Scholar
  9. 9.
    Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14PubMedCrossRefGoogle Scholar
  10. 10.
    Che X, Ye W, Panga L, Wu D-C, Yang G-Y (2001) Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 902:171–7PubMedCrossRefGoogle Scholar
  11. 11.
    Chen H, Song YS, Chan PH (2009) Inhibition of NADPH oxidase is neuroprotective after ischemia–reperfusion. J Cereb Blood Flow Metab 29:1262–72PubMedCrossRefGoogle Scholar
  12. 12.
    Chrissobolis S, Faraci FM (2008) The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med 14:495–502PubMedCrossRefGoogle Scholar
  13. 13.
    Denk A, Wirth T, Baumann B (2000) NF-κB transcription factors: critical regulators of hematopoiesis and neuronal survival. Cytokine Growth Factor Rev 11:303–20PubMedCrossRefGoogle Scholar
  14. 14.
    Didion SP, Faraci FM (2002) Effects of NADH and NADPH on superoxide levels and cerebral vascular tone. Am J Physiol Heart Circ Physiol 282:H688–95PubMedGoogle Scholar
  15. 15.
    Endo H, Kamada H, Nito C, Nishi T, Chan PH (2006) Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci 26:7974–83PubMedCrossRefGoogle Scholar
  16. 16.
    Fahey TJ III, Tracey KJ, Tekamp-Olson P, Cousens LS, Jones WG, Shires GT et al (1992) Macrophage inflammatory protein 1 modulates macrophage function. J Immunol 148:2764–9PubMedGoogle Scholar
  17. 17.
    Fujimura M, Morita-Fujimura Y, Noshita N, Sugawara T, Kawase M, Chan PH (2000) The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice. J Neurosci 20:2817–24PubMedGoogle Scholar
  18. 18.
    Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314PubMedGoogle Scholar
  19. 19.
    Hirano T, Ishihara K, Hibi M (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19:2548–56PubMedCrossRefGoogle Scholar
  20. 20.
    Hoehn B, Yenari MA, Sapolsky RM, Steinberg GK (2003) Glutathione peroxidase overexpression inhibits cytochrome c release and proapoptotic mediators to protect neurons from experimental stroke. Stroke 34:2489–94PubMedCrossRefGoogle Scholar
  21. 21.
    Ishibashi N, Prokopenko O, Reuhl KR, Mirochnitchenko O (2002) Inflammatory response and glutathione peroxidase in a model of stroke. J Immunol 168:1926–33PubMedGoogle Scholar
  22. 22.
    Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD et al (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86PubMedCrossRefGoogle Scholar
  23. 23.
    Jackson SH, Devadas S, Kwon J, Pinto LA, Williams MS (2004) T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol 5:818–27PubMedCrossRefGoogle Scholar
  24. 24.
    Jin RC, Mahoney CE, Coleman Anderson L, Ottaviano F, Croce K, Leopold JA et al (2011) Glutathione peroxidase-3 deficiency promotes platelet-dependent thrombosis in vivo. Circulation 123:1963–73PubMedCrossRefGoogle Scholar
  25. 25.
    Jung JE, Kim GS, Narasimhan P, Song YS, Chan PH (2009) Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia. J Neurosci 29:7003–14PubMedCrossRefGoogle Scholar
  26. 26.
    Jung JE, Kim GS, Chan PH (2011) Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke. Stroke 42:3574–9PubMedCrossRefGoogle Scholar
  27. 27.
    Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA et al (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase–derived radicals. Circ Res 95:1019–26PubMedCrossRefGoogle Scholar
  28. 28.
    Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA et al (1995) Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat. J Neuroimmunol 56:127–34PubMedCrossRefGoogle Scholar
  29. 29.
    Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M et al (2010) Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 8(9):e1000479. doi: 10.1371/journal.pbio.1000479 PubMedCrossRefGoogle Scholar
  30. 30.
    Kontos HA, Wei EP, Povlishock JT, Christman CW (1984) Oxygen radicals mediate the cerebral arteriolar dilation from arachidonate and bradykinin in cats. Circ Res 55:295–303PubMedCrossRefGoogle Scholar
  31. 31.
    Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97PubMedCrossRefGoogle Scholar
  32. 32.
    Li Q, Spencer NY, Oakley FD, Buettner GR, Engelhardt JF (2009) Endosomal Nox2 facilitates redox-dependent induction of NF-κB by TNF-α. Antioxid Redox Signal 11:1249–63PubMedCrossRefGoogle Scholar
  33. 33.
    Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–568PubMedGoogle Scholar
  34. 34.
    Loddick SA, Turnbull AV, Rothwell NJ (1998) Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 18:176–9PubMedCrossRefGoogle Scholar
  35. 35.
    Maeda Y, Matsumoto M, Hori O, Kuwabara K, Ogawa S, Yan SD et al (1994) Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: a paracrine mechanism potentially enhancing neuron survival. J Exp Med 180:2297–308PubMedCrossRefGoogle Scholar
  36. 36.
    Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL et al (2001) Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 104:979–81PubMedCrossRefGoogle Scholar
  37. 37.
    Niizuma K, Endo H, Nito C, Myer DJ, Chan PH (2009) Potential role of PUMA in delayed death of hippocampal CA1 neurons after transient global cerebral ischemia. Stroke 40:618–25PubMedCrossRefGoogle Scholar
  38. 38.
    Nishi T, Maier CM, Hayashi T, Saito A, Chan PH (2005) Superoxide dismutase 1 overexpression reduces MCP-1 and MIP-1α expression after transient focal cerebral ischemia. J Cereb Blood Flow Metab 25:1312–24PubMedCrossRefGoogle Scholar
  39. 39.
    Oka S-I, Kamata H, Kamata K, Yagisawa H, Hirata H (2000) N-Acetylcysteine suppresses TNF-induced NF-κB activation through inhibition of IκB kinases. FEBS Lett 472:196–202PubMedCrossRefGoogle Scholar
  40. 40.
    Park HS, Lee SH, Park D, Lee JS, Ryu SH, Lee WJ et al (2004) Sequential activation of phosphatidylinositol 3-kinase, βPix, Rac1, and Nox1 in growth factor-induced production of H2O2. Mol Cell Biol 24:4384–94PubMedCrossRefGoogle Scholar
  41. 41.
    Sakata H, Narasimhan P, Niizuma K, Maier CM, Wakai T, Chan PH (2012) Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice. Brain 135:3298–310PubMedCrossRefGoogle Scholar
  42. 42.
    Sakata H, Niizuma K, Yoshioka H, Kim GS, Jung JE, Katsu M et al (2012) Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 32:3462–73PubMedCrossRefGoogle Scholar
  43. 43.
    Shih AY, Li P, Murphy TH (2005) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 25:10321–35PubMedCrossRefGoogle Scholar
  44. 44.
    Song YS, Lee Y-S, Chan PH (2005) Oxidative stress transiently decreases the IKK complex (IKKα, β, and γ), an upstream component of NF-κB signaling, after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25:1301–11PubMedCrossRefGoogle Scholar
  45. 45.
    Suzuki S, Tanaka K, Suzuki N (2009) Ambivalent aspects of interleukin-6 in cerebral ischemia: inflammatory versus neurotrophic aspects. J Cereb Blood Flow Metab 29:464–79PubMedCrossRefGoogle Scholar
  46. 46.
    Touzani O, Boutin H, LeFeuvre R, Parker L, Miller A, Luheshi G et al (2002) Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor. J Neurosci 22:38–43PubMedGoogle Scholar
  47. 47.
    Vila N, Castillo J, Dávalos A, Chamorro A (2000) Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31:2325–9PubMedCrossRefGoogle Scholar
  48. 48.
    Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68PubMedCrossRefGoogle Scholar
  49. 49.
    Wang HK, Park UJ, Kim SY, Lee JH, Kim SU, Gwag BJ et al (2008) Free radical production in CA1 neurons induces MIP-1α expression, microglia recruitment, and delayed neuronal death after transient forebrain ischemia. J Neurosci 28:1721–7PubMedCrossRefGoogle Scholar
  50. 50.
    Yamashita T, Sawamoto K, Suzuki S, Suzuki N, Adachi K, Kawase T et al (2005) Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 94:459–68PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM et al (1995) Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438–42PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Purnima Narasimhan
    • 1
  • Hiroyuki Sakata
    • 1
  • Joo Eun Jung
    • 1
  • Tatsuro Nishi
    • 1
  • Takuma Wakai
    • 1
  • Carolina M. Maier
    • 1
  • Pak H. Chan
    • 1
  1. 1.Stanford University School of MedicineStanfordUSA

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