Arachidonic Acid Metabolism and Lipid Peroxidation in Stroke: Alpha-Tocotrienol as a Unique Therapeutic Agent

  • Cameron Rink
  • Savita Khanna
  • Chandan K. SenEmail author
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Under normal physiological conditions, the human brain has one of the highest metabolic profiles of all organs, using 25% of glucose and 20% of all oxygen consumed by the body. When challenged by metabolic disruption as in ischemic or hemorrhagic stroke, brain tissue that is enriched with arachidonic acid (22:6n − 3 polyunsaturated fatty acid) is highly susceptible to oxidative stress. The consequence of increased generation of radical species in stroke-affected brain tissue is the uncontrolled oxidative metabolism of arachidonic acid, generating a host of secondary products that are culpable neuromodulators of the cell death cascade. In this chapter, preclinical models of ischemic and hemorrhagic stroke injury are explored. Subsequently, the arachidonic acid cascade is examined as a common pathological contributor of oxidative stress in both aforementioned stroke subtypes. Finally, the unique neuroprotective properties of the natural vitamin E alpha-tocotrienol are discussed as a potent intervention of the stroke-induced arachidonic acid cascade.


Alpha-tocotrienol Arachidonic acid Ischemia Lipid peroxidation ROS Stroke Vitamin E 



Supported by NIH NS42617 to CKS.


  1. 1.
    McKay, J., Mensah, G.A. & ebrary Inc. The atlas of heart disease and stroke. 112 p. (World Health Organization, Geneva, 2005).Google Scholar
  2. 2.
    Lloyd-Jones, D. et al. Heart Disease and Stroke Statistics--2010 Update. A Report From the American Heart Association. Circulation (2009).Google Scholar
  3. 3.
    Thrombolytic therapy for acute ischemic stroke. Cjem 3, 8–12 (2001).Google Scholar
  4. 4.
    Hills, N.K. & Johnston, S.C. Why are eligible thrombolysis candidates left untreated? Am J Prev Med 31, S210–6 (2006).PubMedCrossRefGoogle Scholar
  5. 5.
    Kleindorfer, D. et al. US geographic distribution of rt-PA utilization by hospital for acute ischemic stroke. Stroke 40, 3580–4 (2009).PubMedCrossRefGoogle Scholar
  6. 6.
    Rother, J. Neuroprotection does not work! Stroke 39, 523–4 (2008).Google Scholar
  7. 7.
    Savitz, S.I. & Fisher, M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol 61, 396–402 (2007).PubMedCrossRefGoogle Scholar
  8. 8.
    Young, A.R., Ali, C., Duretete, A. & Vivien, D. Neuroprotection and stroke: time for a compromise. J Neurochem 103, 1302–9 (2007).PubMedCrossRefGoogle Scholar
  9. 9.
    Cherubini, A., Ruggiero, C., Polidori, M.C. & Mecocci, P. Potential markers of oxidative stress in stroke. Free Radic Biol Med 39, 841–52 (2005).PubMedCrossRefGoogle Scholar
  10. 10.
    Gusnard, D.A., Raichle, M.E. & Raichle, M.E. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2, 685–94 (2001).PubMedCrossRefGoogle Scholar
  11. 11.
    Zauner, A., Daugherty, W.P., Bullock, M.R. & Warner, D.S. Brain oxygenation and energy metabolism: part I-biological function and pathophysiology. Neurosurgery 51, 289–301; discussion 302 (2002).Google Scholar
  12. 12.
    Boveris, A. & Chance, B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134, 707–16 (1973).Google Scholar
  13. 13.
    Turrens, J.F. Superoxide production by the mitochondrial respiratory chain. Biosci Rep 17, 3–8 (1997).PubMedCrossRefGoogle Scholar
  14. 14.
    Sorrenti, V., Di Giacomo, C., Campisi, A., Perez-Polo, J.R. & Vanella, A. Nitric oxide synthetase activity in cerebral post-ischemic reperfusion and effects of L-N(G)-nitroarginine and 7-nitroindazole on the survival. Neurochem Res 24, 861–6 (1999).PubMedCrossRefGoogle Scholar
  15. 15.
    Sorrenti, V. et al. Imidazole derivatives as antioxidants and selective inhibitors of nNOS. Nitric Oxide 14, 45–50 (2006).PubMedCrossRefGoogle Scholar
  16. 16.
    Lizasoain, I., Moro, M.A., Knowles, R.G., Darley-Usmar, V. & Moncada, S. Nitric oxide and peroxynitrite exert distinct effects on mitochondrial respiration which are differentially blocked by glutathione or glucose. Biochem J 314 (Pt 3), 877–80 (1996).PubMedGoogle Scholar
  17. 17.
    Virag, L., Szabo, E., Gergely, P. & Szabo, C. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 140-141, 113–24 (2003).PubMedCrossRefGoogle Scholar
  18. 18.
    Kidwell, C.S., Liebeskind, D.S., Starkman, S. & Saver, J.L. Trends in acute ischemic stroke trials through the 20th century. Stroke 32, 1349–59 (2001).PubMedCrossRefGoogle Scholar
  19. 19.
    Schmid-Elsaesser, R., Zausinger, S., Hungerhuber, E., Baethmann, A. & Reulen, H.J. A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry. Stroke 29, 2162–70 (1998).PubMedCrossRefGoogle Scholar
  20. 20.
    Koizumi J, Y.Y., Nakazawa T, Ooneda G. Experimental studies of ischemic brain edema. I. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 8, 1–8 (1986).CrossRefGoogle Scholar
  21. 21.
    Longa, E.Z., Weinstein, P.R., Carlson, S. & Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84–91 (1989).PubMedCrossRefGoogle Scholar
  22. 22.
    Busch, E., Kruger, K. & Hossmann, K.A. Improved model of thromboembolic stroke and rt-PA induced reperfusion in the rat. Brain Res 778, 16–24 (1997).PubMedCrossRefGoogle Scholar
  23. 23.
    Gerriets, T. et al. The macrosphere model: evaluation of a new stroke model for permanent middle cerebral artery occlusion in rats. in J Neurosci Methods Vol. 122 201–11 (2003).Google Scholar
  24. 24.
    Umemura, K. & Nakashima, M. [A new model of middle cerebral artery thrombosis in rats]. Yakubutsu Seishin Kodo 13, 9–17 (1993).PubMedGoogle Scholar
  25. 25.
    Belayev, L., Alonso, O.F., Busto, R., Zhao, W. & Ginsberg, M.D. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. in Stroke Vol. 27 1616–22; discussion 1623 (1996).Google Scholar
  26. 26.
    Garcia, J.H., Wagner, S., Liu, K.F. & Hu, X.J. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke 26, 627–34; discussion 635 (1995).Google Scholar
  27. 27.
    Kawamura, S., Li, Y., Shirasawa, M., Yasui, N. & Fukasawa, H. Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg Neurol 41, 368–73 (1994).PubMedCrossRefGoogle Scholar
  28. 28.
    Kawamura, S., Yasui, N., Shirasawa, M. & Fukasawa, H. Rat middle cerebral artery occlusion using an intraluminal thread technique. Acta Neurochir (Wien) 109, 126–32 (1991).Google Scholar
  29. 29.
    Memezawa, H., Smith, M.L. & Siesjo, B.K. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23, 552–9 (1992).PubMedCrossRefGoogle Scholar
  30. 30.
    Lodder, J. Neuroprotection in stroke: Analysis of failure, and alternative strategies. Neurosci Res Commun 26, p. 173–179 (2000).CrossRefGoogle Scholar
  31. 31.
    Gerriets, T. et al. Complications and pitfalls in rat stroke models for middle cerebral artery occlusion: a comparison between the suture and the macrosphere model using magnetic resonance angiography. Stroke 35, 2372–7 (2004).PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang, K. & Sejnowski, T.J. A universal scaling law between gray matter and white matter of cerebral cortex. Proc Natl Acad Sci USA 97, 5621–6 (2000).PubMedCrossRefGoogle Scholar
  33. 33.
    Traystman, R.J. Animal models of focal and global cerebral ischemia. Ilar J 44, 85-95 (2003).PubMedCrossRefGoogle Scholar
  34. 34.
    Rink, C. et al. Minimally invasive neuroradiologic model of preclinical transient middle cerebral artery occlusion in canines. in Proc Natl Acad Sci USA Vol. 105 14100–5 (2008).Google Scholar
  35. 35.
    Crowell, R.M., Olsson, Y., Klatzo, I. & Ommaya, A. Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke 1, 439–48 (1970).PubMedCrossRefGoogle Scholar
  36. 36.
    Frazee, J.G. et al. Retrograde transvenous neuroperfusion: a back door treatment for stroke. Stroke 29, 1912–6 (1998).PubMedCrossRefGoogle Scholar
  37. 37.
    Huang, J. et al. A modified transorbital baboon model of reperfused stroke. Stroke 31, 3054–63 (2000).PubMedCrossRefGoogle Scholar
  38. 38.
    Young, A.R. et al. Early reperfusion in the anesthetized baboon reduces brain damage following middle cerebral artery occlusion: a quantitative analysis of infarction volume. Stroke 28, 632–7; discussion 637–8 (1997).Google Scholar
  39. 39.
    Ducruet, A.F. et al. Pre-clinical evaluation of an sLe x-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke. in J Med Primatol Vol. 36 375–80 (2007).Google Scholar
  40. 40.
    Goettler, C.E. & Tucci, K.A. Decreasing the morbidity of decompressive craniectomy: the Tucci flap. J Trauma 62, 777–8 (2007).PubMedCrossRefGoogle Scholar
  41. 41.
    Jiang, J.Y. et al. Efficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: a multicenter, prospective, randomized controlled study. J Neurotrauma 22, 623–8 (2005).PubMedCrossRefGoogle Scholar
  42. 42.
    Quigley, M. Non-human primates: the appropriate subjects of biomedical research? J Med Ethics 33, 655–8 (2007).PubMedCrossRefGoogle Scholar
  43. 43.
    Bhogal, N., Hudson, M., Balls, M. & Combes, R.D. The use of non-human primates in biological and medical research: evidence submitted by FRAME to the Academy of Medical Sciences/Medical Research Council/Royal Society/Wellcome Trust Working Group. Altern Lab Anim 33, 519–27 (2005).PubMedGoogle Scholar
  44. 44.
    Hua, Y., Keep, R.F., Hoff, J.T. & Xi, G. Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke 38, 759–62 (2007).PubMedCrossRefGoogle Scholar
  45. 45.
    Huang, F.P. et al. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg 96, 287–93 (2002).PubMedCrossRefGoogle Scholar
  46. 46.
    Sadrzadeh, S.M., Anderson, D.K., Panter, S.S., Hallaway, P.E. & Eaton, J.W. Hemoglobin potentiates central nervous system damage. J Clin Invest 79, 662–4 (1987).PubMedCrossRefGoogle Scholar
  47. 47.
    Sadrzadeh, S.M. & Eaton, J.W. Hemoglobin-mediated oxidant damage to the central nervous system requires endogenous ascorbate. J Clin Invest 82, 1510–5 (1988).PubMedCrossRefGoogle Scholar
  48. 48.
    Stankiewicz, J.M. & Brass, S.D. Role of iron in neurotoxicity: a cause for concern in the elderly? Curr Opin Clin Nutr Metab Care 12, 22–9 (2009).PubMedCrossRefGoogle Scholar
  49. 49.
    Aviv, R.I. et al. Hemorrhagic transformation of ischemic stroke: prediction with CT perfusion. Radiology 250, 867–77 (2009).PubMedCrossRefGoogle Scholar
  50. 50.
    Lapchak, P.A. Hemorrhagic transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep 2, 38–43 (2002).PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang, J. & Piantadosi, C.A. Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 90, 1193–9 (1992).PubMedCrossRefGoogle Scholar
  52. 52.
    James, M.L., Warner, D.S. & Laskowitz, D.T. Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care 9, 139–52 (2008).PubMedCrossRefGoogle Scholar
  53. 53.
    Britt, R.H. et al. Correlation of neuropathologic findings, computerized tomographic and high-resolution ultrasound scans of canine avian sarcoma virus-induced brain tumors. J Neurooncol 4, 243–68 (1987).PubMedCrossRefGoogle Scholar
  54. 54.
    Rosenberg, G.A., Estrada, E., Wesley, M. & Kyner, W.T. Autoradiographic patterns of brain interstitial fluid flow after collagenase-induced haemorrhage in rat. Acta Neurochir Suppl (Wien) 51, 280–2 (1990).Google Scholar
  55. 55.
    Strbian, D., Durukan, A. & Tatlisumak, T. Rodent models of hemorrhagic stroke. Curr Pharm Des 14, 352–8 (2008).PubMedCrossRefGoogle Scholar
  56. 56.
    Ducruet, A.F. et al. The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp Neurol 219, 398–403 (2009).PubMedCrossRefGoogle Scholar
  57. 57.
    Kleinig, T.J. & Vink, R. Suppression of inflammation in ischemic and hemorrhagic stroke: therapeutic options. Curr Opin Neurol 22, 294–301 (2009).PubMedCrossRefGoogle Scholar
  58. 58.
    Yang, G.Y., Betz, A.L., Chenevert, T.L., Brunberg, J.A. & Hoff, J.T. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 81, 93–102 (1994).PubMedCrossRefGoogle Scholar
  59. 59.
    Bederson, J.B., Germano, I.M. & Guarino, L. Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke 26, 1086–91; discussion 1091–2 (1995).Google Scholar
  60. 60.
    Veelken, J.A., Laing, R.J. & Jakubowski, J. The Sheffield model of subarachnoid hemorrhage in rats. Stroke 26, 1279–83; discussion 1284 (1995).Google Scholar
  61. 61.
    Cooper, A.J. & Kristal, B.S. Multiple roles of glutathione in the central nervous system. Biol Chem 378, 793–802 (1997).PubMedGoogle Scholar
  62. 62.
    Contreras, M.A. et al. Nutritional deprivation of alpha-linolenic acid decreases but does not abolish turnover and availability of unacylated docosahexaenoic acid and docosahexaenoyl-CoA in rat brain. J Neurochem 75, 2392–400 (2000).PubMedCrossRefGoogle Scholar
  63. 63.
    Carlson, S.E., Werkman, S.H., Peeples, J.M., Cooke, R.J. & Tolley, E.A. Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci U S A 90, 1073–7 (1993).PubMedCrossRefGoogle Scholar
  64. 64.
    Carlson, S.E., Werkman, S.H., Peeples, J.M. & Wilson, W.M. Long-chain fatty acids and early visual and cognitive development of preterm infants. Eur J Clin Nutr 48 Suppl 2, S27–30 (1994).PubMedGoogle Scholar
  65. 65.
    Carlson, S.E., Werkman, S.H., Peeples, J.M. & Wilson, W.M., 3rd. Growth and development of premature infants in relation to omega 3 and omega 6 fatty acid status. World Rev Nutr Diet 75, 63–9 (1994).PubMedGoogle Scholar
  66. 66.
    Neuringer, M., Connor, W.E., Lin, D.S., Barstad, L. & Luck, S. Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci USA 83, 4021–5 (1986).PubMedCrossRefGoogle Scholar
  67. 67.
    Rapoport, S.I., Chang, M.C. & Spector, A.A. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res 42, 678–85 (2001).PubMedGoogle Scholar
  68. 68.
    Uauy, R.D., Birch, D.G., Birch, E.E., Tyson, J.E. & Hoffman, D.R. Effect of dietary omega-3 fatty acids on retinal function of very-low-birth-weight neonates. Pediatr Res 28, 485–92 (1990).PubMedCrossRefGoogle Scholar
  69. 69.
    Eichberg, J. Phospholipids in nervous tissues, xviii, 386 p. (Wiley, New York, 1985).Google Scholar
  70. 70.
    Jones, C.R., Arai, T. & Rapoport, S.I. Evidence for the involvement of docosahexaenoic acid in cholinergic stimulated signal transduction at the synapse. Neurochem Res 22, 663–70 (1997).PubMedCrossRefGoogle Scholar
  71. 71.
    Young, C., Gean, P.W., Wu, S.P., Lin, C.H. & Shen, Y.Z. Cancellation of low-frequency stimulation-induced long-term depression by docosahexaenoic acid in the rat hippocampus. Neurosci Lett 247, 198–200 (1998).PubMedCrossRefGoogle Scholar
  72. 72.
    Spector, A.A. Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain. J Mol Neurosci 16, 159–65; discussion 215–21 (2001).Google Scholar
  73. 73.
    Farooqui, A.A., Horrocks, L.A. & Farooqui, T. Modulation of inflammation in brain: a matter of fat. J Neurochem 101, 577–99 (2007).PubMedCrossRefGoogle Scholar
  74. 74.
    Rapoport, S.I. Arachidonic acid and the brain. J Nutr 138, 2515–20 (2008).PubMedGoogle Scholar
  75. 75.
    Burke, J.E. & Dennis, E.A. Phospholipase A2 biochemistry. Cardiovasc Drugs Ther 23, 49–59 (2009).PubMedCrossRefGoogle Scholar
  76. 76.
    Adibhatla, R.M. & Hatcher, J.F. Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. BMB Rep 41, 560–7 (2008).PubMedCrossRefGoogle Scholar
  77. 77.
    Adibhatla, R.M., Hatcher, J.F. & Dempsey, R.J. Phospholipase A2, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal 5, 647–54 (2003).PubMedCrossRefGoogle Scholar
  78. 78.
    Clemens, J.A. et al. Reactive glia express cytosolic phospholipase A2 after transient global forebrain ischemia in the rat. Stroke 27, 527–35 (1996).PubMedCrossRefGoogle Scholar
  79. 79.
    Owada, Y., Tominaga, T., Yoshimoto, T. & Kondo, H. Molecular cloning of rat cDNA for cytosolic phospholipase A2 and the increased gene expression in the dentate gyrus following transient forebrain ischemia. Brain Res Mol Brain Res 25, 364–8 (1994).PubMedCrossRefGoogle Scholar
  80. 80.
    Lauritzen, I., Heurteaux, C. & Lazdunski, M. Expression of group II phospholipase A2 in rat brain after severe forebrain ischemia and in endotoxic shock. Brain Res 651, 353–6 (1994).PubMedCrossRefGoogle Scholar
  81. 81.
    Umemura, A., Mabe, H., Nagai, H. & Sugino, F. Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist. J Neurosurg 76, 648–51 (1992).Google Scholar
  82. 82.
    Saluja, I., Song, D., O’Regan, M.H. & Phillis, J.W. Role of phospholipase A2 in the release of free fatty acids during ischemia-reperfusion in the rat cerebral cortex. Neurosci Lett 233, 97–100 (1997).PubMedCrossRefGoogle Scholar
  83. 83.
    Stephenson, D. et al. Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration. Glia 27, 110–28 (1999).PubMedCrossRefGoogle Scholar
  84. 84.
    Rordorf, G., Uemura, Y. & Bonventre, J.V. Characterization of phospholipase A2 (PLA2) activity in gerbil brain: enhanced activities of cytosolic, mitochondrial, and microsomal forms after ischemia and reperfusion. J Neurosci 11, 1829–36 (1991).PubMedGoogle Scholar
  85. 85.
    Lin, T.N. et al. Induction of secretory phospholipase A2 in reactive astrocytes in response to transient focal cerebral ischemia in the rat brain. J Neurochem 90, 637–45 (2004).PubMedCrossRefGoogle Scholar
  86. 86.
    Hirashima, Y., Endo, S., Ohmori, T., Kato, R. & Takaku, A. Platelet-activating factor (PAF) concentration and PAF acetylhydrolase activity in cerebrospinal fluid of patients with subarachnoid hemorrhage. J Neurosurg 80, 31–6 (1994).PubMedCrossRefGoogle Scholar
  87. 87.
    Adibhatla, R.M. et al. CDP-choline significantly restores phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP: phosphocholine cytidylyltransferase after stroke. J Biol Chem 281, 6718–25 (2006).PubMedCrossRefGoogle Scholar
  88. 88.
    Anthonsen, M.W., Solhaug, A. & Johansen, B. Functional coupling between secretory and cytosolic phospholipase A2 modulates tumor necrosis factor-alpha- and interleukin-1beta-induced NF-kappa B activation. J Biol Chem 276, 30527–36 (2001).PubMedCrossRefGoogle Scholar
  89. 89.
    Burke, J.E. & Dennis, E.A. Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50 Suppl, S237–42 (2009).PubMedCrossRefGoogle Scholar
  90. 90.
    Stephenson, D.T. et al. Calcium-sensitive cytosolic phospholipase A2 (cPLA2) is expressed in human brain astrocytes. Brain Res 637, 97–105 (1994).PubMedCrossRefGoogle Scholar
  91. 91.
    Yoshihara, Y. & Watanabe, Y. Translocation of phospholipase A2 from cytosol to membranes in rat brain induced by calcium ions. Biochem Biophys Res Commun 170, 484–90 (1990).PubMedCrossRefGoogle Scholar
  92. 92.
    Lin, L.L. et al. cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269–78 (1993).PubMedCrossRefGoogle Scholar
  93. 93.
    Xu, J. et al. Role of PKC and MAPK in cytosolic PLA2 phosphorylation and arachadonic acid release in primary murine astrocytes. J Neurochem 83, 259–70 (2002).PubMedCrossRefGoogle Scholar
  94. 94.
    Nito, C. et al. Role of the p38 mitogen-activated protein kinase/cytosolic phospholipase A2 signaling pathway in blood-brain barrier disruption after focal cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 28, 1686–96 (2008).PubMedCrossRefGoogle Scholar
  95. 95.
    Sun, G.Y. & Foudin, L.L. On the status of lysolecithin in rat cerebral cortex during ischemia. J Neurochem 43, 1081–6 (1984).PubMedCrossRefGoogle Scholar
  96. 96.
    Kinouchi, H., Imaizumi, S., Yoshimoto, T., Yamamoto, H. & Motomiya, M. Changes of polyphosphoinositides, lysophospholipid, and free fatty acids in transient cerebral ischemia of rat brain. Mol Chem Neuropathol 12, 215–28 (1990).PubMedCrossRefGoogle Scholar
  97. 97.
    Hirashima, Y. et al. Elevation of platelet activating factor, inflammatory cytokines, and coagulation factors in the internal jugular vein of patients with subarachnoid hemorrhage. Neurochem Res 22, 1249–55 (1997).PubMedCrossRefGoogle Scholar
  98. 98.
    Stock, C., Schilling, T., Schwab, A. & Eder, C. Lysophosphatidylcholine stimulates IL-1beta release from microglia via a P2X7 receptor-independent mechanism. J Immunol 177, 8560–8 (2006).PubMedGoogle Scholar
  99. 99.
    Ousman, S.S. & David, S. Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia 30, 92–104 (2000).PubMedCrossRefGoogle Scholar
  100. 100.
    Schilling, T., Lehmann, F., Ruckert, B. & Eder, C. Physiological mechanisms of lysophosphatidylcholine-induced de-ramification of murine microglia. J Physiol 557, 105–20 (2004).PubMedCrossRefGoogle Scholar
  101. 101.
    Phillis, J.W., Horrocks, L.A. & Farooqui, A.A. Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev 52, 201–43 (2006).PubMedCrossRefGoogle Scholar
  102. 102.
    Beal, M.F., Howell, N. & Bodis-Wollner, I. Mitochondria and free radicals in neurodegenerative diseases, xii, 610 p. (Wiley-Liss, New York, 1997).Google Scholar
  103. 103.
    Adibhatla, R.M., Hatcher, J.F. & Dempsey, R.J. Lipids and lipidomics in brain injury and diseases. Aaps J 8, E314–21 (2006).PubMedGoogle Scholar
  104. 104.
    Esterbauer, H., Schaur, R.J. & Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11, 81–128 (1991).PubMedCrossRefGoogle Scholar
  105. 105.
    Kehrer, J.P. & Biswal, S.S. The molecular effects of acrolein. Toxicol Sci 57, 6–15 (2000).PubMedCrossRefGoogle Scholar
  106. 106.
    Parola, M., Bellomo, G., Robino, G., Barrera, G. & Dianzani, M.U. 4-Hydroxynonenal as a biological signal: molecular basis and pathophysiological implications. Antioxid Redox Signal 1, 255–84 (1999).PubMedCrossRefGoogle Scholar
  107. 107.
    Farooqui, A.A., Ong, W.Y. & Horrocks, L.A. Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev 58, 591–620 (2006).PubMedCrossRefGoogle Scholar
  108. 108.
    Keller, J.N. et al. 4-Hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80, 685–96 (1997).PubMedCrossRefGoogle Scholar
  109. 109.
    Mark, R.J., Pang, Z., Geddes, J.W., Uchida, K. & Mattson, M.P. Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J Neurosci 17, 1046–54 (1997).PubMedGoogle Scholar
  110. 110.
    Miyake, H., Kadoya, A. & Ohyashiki, T. Increase in molecular rigidity of the protein conformation of brain Na+-K+-ATPase by modification with 4-hydroxy-2-nonenal. Biol Pharm Bull 26, 1652–6 (2003).PubMedCrossRefGoogle Scholar
  111. 111.
    Grimsrud, P.A., Xie, H., Griffin, T.J. & Bernlohr, D.A. Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem 283, 21837–41 (2008).PubMedCrossRefGoogle Scholar
  112. 112.
    Fang, J. & Holmgren, A. Inhibition of thioredoxin and thioredoxin reductase by 4-hydroxy-2-nonenal in vitro and in vivo. J Am Chem Soc 128, 1879–85 (2006).PubMedCrossRefGoogle Scholar
  113. 113.
    Musiek, E.S. et al. Cyclopentenone isoprostanes are novel bioactive products of lipid oxidation which enhance neurodegeneration. J Neurochem 97, 1301–13 (2006).PubMedCrossRefGoogle Scholar
  114. 114.
    Zeiger, S.L. et al. Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury. Free Radic Biol Med 47, 1422–31 (2009).PubMedCrossRefGoogle Scholar
  115. 115.
    Lahaie, I. et al. A novel mechanism for vasoconstrictor action of 8-isoprostaglandin F2 alpha on retinal vessels. Am J Physiol 274, R1406–16 (1998).PubMedGoogle Scholar
  116. 116.
    Simmons, D.L., Botting, R.M. & Hla, T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56, 387–437 (2004).PubMedCrossRefGoogle Scholar
  117. 117.
    Kukreja, R.C., Kontos, H.A., Hess, M.L. & Ellis, E.F. PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH. Circ Res 59, 612–9 (1986).PubMedCrossRefGoogle Scholar
  118. 118.
    Smith, W.L., Garavito, R.M. & DeWitt, D.L. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 271, 33157–60 (1996).PubMedCrossRefGoogle Scholar
  119. 119.
    Im, J.Y., Kim, D., Paik, S.G. & Han, P.L. Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. Free Radic Biol Med 41, 960–72 (2006).PubMedCrossRefGoogle Scholar
  120. 120.
    Iadecola, C. & Gorelick, P.B. The Janus face of cyclooxygenase-2 in ischemic stroke: shifting toward downstream targets. Stroke 36, 182–5 (2005).PubMedCrossRefGoogle Scholar
  121. 121.
    Chopra, B. et al. Cyclooxygenase-1 is a marker for a subpopulation of putative nociceptive neurons in rat dorsal root ganglia. Eur J Neurosci 12, 911–20 (2000).PubMedCrossRefGoogle Scholar
  122. 122.
    Goppelt-Struebe, M. & Beiche, F. Cyclooxygenase-2 in the spinal cord: localization and regulation after a peripheral inflammatory stimulus. Adv Exp Med Biol 433, 213–6 (1997).PubMedGoogle Scholar
  123. 123.
    Deininger, M.H., Kremsner, P.G., Meyermann, R. & Schluesener, H.J. Focal accumulation of cyclooxygenase-1 (COX-1) and COX-2 expressing cells in cerebral malaria. J Neuroimmunol 106, 198–205 (2000).PubMedCrossRefGoogle Scholar
  124. 124.
    McGeer, P.L., McGeer, E.G. & Yasojima, K. Expression of COX-1 and COX-2 mRNAs in atherosclerotic plaques. Exp Gerontol 37, 925–9 (2002).PubMedCrossRefGoogle Scholar
  125. 125.
    Iadecola, C., Forster, C., Nogawa, S., Clark, H.B. & Ross, M.E. Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia. Acta Neuropathol 98, 9–14 (1999).PubMedCrossRefGoogle Scholar
  126. 126.
    Miettinen, S. et al. Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci USA 94, 6500–5 (1997).PubMedCrossRefGoogle Scholar
  127. 127.
    Nakayama, M. et al. Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proc Natl Acad Sci USA 95, 10954–9 (1998).PubMedCrossRefGoogle Scholar
  128. 128.
    Nogawa, S., Zhang, F., Ross, M.E. & Iadecola, C. Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 17, 2746–55 (1997).PubMedGoogle Scholar
  129. 129.
    Osuka, K. et al. Activation of the JAK-STAT signaling pathway in the rat basilar artery after subarachnoid hemorrhage. Brain Res 1072, 1–7 (2006).PubMedCrossRefGoogle Scholar
  130. 130.
    Sapirstein, A. & Bonventre, J.V. Phospholipases A2 in ischemic and toxic brain injury. Neurochem Res 25, 745–53 (2000).PubMedCrossRefGoogle Scholar
  131. 131.
    Tabuchi, S. et al. Mice deficient in cytosolic phospholipase A2 are less susceptible to cerebral ischemia/reperfusion injury. Acta Neurochir Suppl 86, 169–72 (2003).PubMedCrossRefGoogle Scholar
  132. 132.
    Takano, T., Panesar, M., Papillon, J. & Cybulsky, A.V. Cyclooxygenases-1 and 2 couple to cytosolic but not group IIA phospholipase A2 in COS-1 cells. Prostaglandins Other Lipid Mediat 60, 15–26 (2000).PubMedCrossRefGoogle Scholar
  133. 133.
    Naraba, H. et al. Segregated coupling of phospholipases A2, cyclooxygenases, and terminal prostanoid synthases in different phases of prostanoid biosynthesis in rat peritoneal macrophages. J Immunol 160, 2974–82 (1998).PubMedGoogle Scholar
  134. 134.
    Scott, K.F., Bryant, K.J. & Bidgood, M.J. Functional coupling and differential regulation of the phospholipase A2-cyclooxygenase pathways in inflammation. J Leukoc Biol 66, 535–41 (1999).PubMedGoogle Scholar
  135. 135.
    Kurumbail, R.G. et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384, 644–8 (1996).PubMedCrossRefGoogle Scholar
  136. 136.
    Smith, W.L., DeWitt, D.L. & Garavito, R.M. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69, 145–82 (2000).PubMedCrossRefGoogle Scholar
  137. 137.
    Kis, B., Snipes, J.A., Isse, T., Nagy, K. & Busija, D.W. Putative cyclooxygenase-3 expression in rat brain cells. J Cereb Blood Flow Metab 23, 1287–92 (2003).PubMedCrossRefGoogle Scholar
  138. 138.
    Chandrasekharan, N.V. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 99, 13926–31 (2002).PubMedCrossRefGoogle Scholar
  139. 139.
    Stevens, M.K. & Yaksh, T.L. Time course of release in vivo of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and TxB2 into the brain extracellular space after 15 min of complete global ischemia in the presence and absence of cyclooxygenase inhibition. J Cereb Blood Flow Metab 8, 790–8 (1988).PubMedCrossRefGoogle Scholar
  140. 140.
    Liang, X. et al. Function of COX-2 and prostaglandins in neurological disease. J Mol Neurosci 33, 94–9 (2007).PubMedCrossRefGoogle Scholar
  141. 141.
    Kawano, T. et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12, 225–9 (2006).PubMedCrossRefGoogle Scholar
  142. 142.
    McCullough, L. et al. Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. J Neurosci 24, 257–68 (2004).PubMedCrossRefGoogle Scholar
  143. 143.
    Hamberg, M. & Samuelsson, B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc Natl Acad Sci USA 71, 3400–4 (1974).CrossRefGoogle Scholar
  144. 144.
    Aparoy, P., Reddy, R.N., Guruprasad, L., Reddy, M.R. & Reddanna, P. Homology modeling of 5-lipoxygenase and hints for better inhibitor design. J Comput Aided Mol Des 22, 611–9 (2008).PubMedCrossRefGoogle Scholar
  145. 145.
    Glickman, M.H. & Klinman, J.P. Lipoxygenase reaction mechanism: demonstration that hydrogen abstraction from substrate precedes dioxygen binding during catalytic turnover. Biochemistry 35, 12882–92 (1996).PubMedCrossRefGoogle Scholar
  146. 146.
    Hambrecht, G.S., Adesuyi, S.A., Holt, S. & Ellis, E.F. Brain 12-HETE formation in different species, brain regions, and in brain microvessels. Neurochem Res 12, 1029–33 (1987).PubMedCrossRefGoogle Scholar
  147. 147.
    Bendani, M.K. et al. Localization of 12-lipoxygenase mRNA in cultured oligodendrocytes and astrocytes by in situ reverse transcriptase and polymerase chain reaction. Neurosci Lett 189, 159–62 (1995).PubMedCrossRefGoogle Scholar
  148. 148.
    Katsuki, H. & Okuda, S. Arachidonic acid as a neurotoxic and neurotrophic substance. Prog Neurobiol 46, 607–36 (1995).PubMedCrossRefGoogle Scholar
  149. 149.
    Canals, S., Casarejos, M.J., de Bernardo, S., Rodriguez-Martin, E. & Mena, M.A. Nitric oxide triggers the toxicity due to glutathione depletion in midbrain cultures through 12-lipoxygenase. J Biol Chem 278, 21542–9 (2003).PubMedCrossRefGoogle Scholar
  150. 150.
    Kramer, B.C. et al. Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites. Eur J Neurosci 19, 280–6 (2004).PubMedCrossRefGoogle Scholar
  151. 151.
    Nazarewicz, R.R. et al. 12(S)-hydroperoxyeicosatetraenoic acid (12-HETE) increases mitochondrial nitric oxide by increasing intramitochondrial calcium. Arch Biochem Biophys 468, 114–20 (2007).PubMedCrossRefGoogle Scholar
  152. 152.
    Hariri, R.J. et al. Human glial cell production of lipoxygenase-generated eicosanoids: a potential role in the pathophysiology of vascular changes following traumatic brain injury. J Trauma 29, 1203–10 (1989).PubMedCrossRefGoogle Scholar
  153. 153.
    Jin, G. et al. Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke 39, 2538–43 (2008).PubMedCrossRefGoogle Scholar
  154. 154.
    Shimizu, T. & Wolfe, L.S. Arachidonic acid cascade and signal transduction. J Neurochem 55, 1–15 (1990).PubMedCrossRefGoogle Scholar
  155. 155.
    Unterberg, A., Schmidt, W., Wahl, M. & Baethmann, A. Role of leukotrienes as mediator compounds in brain edema. Adv Neurol 52, 211–4 (1990).PubMedGoogle Scholar
  156. 156.
    Rao, A.M., Hatcher, J.F., Kindy, M.S. & Dempsey, R.J. Arachidonic acid and leukotriene C4: role in transient cerebral ischemia of gerbils. Neurochem Res 24, 1225–32 (1999).PubMedCrossRefGoogle Scholar
  157. 157.
    Canetti, C., Hu, B., Curtis, J.L. & Peters-Golden, M. Syk activation is a leukotriene B4-regulated event involved in macrophage phagocytosis of IgG-coated targets but not apoptotic cells. Blood 102, 1877–83 (2003).PubMedCrossRefGoogle Scholar
  158. 158.
    Coffey, M.J., Phare, S.M. & Peters-Golden, M. Role of leukotrienes in killing of Mycobacterium bovis by neutrophils. Prostaglandins Leukot Essent Fatty Acids 71, 185–90 (2004).PubMedCrossRefGoogle Scholar
  159. 159.
    Flamand, N., Mancuso, P., Serezani, C.H. & Brock, T.G. Leukotrienes: mediators that have been typecast as villains. Cell Mol Life Sci 64, 2657–70 (2007).PubMedCrossRefGoogle Scholar
  160. 160.
    Serezani, C.H., Perrela, J.H., Russo, M., Peters-Golden, M. & Jancar, S. Leukotrienes are essential for the control of Leishmania amazonensis infection and contribute to strain variation in susceptibility. J Immunol 177, 3201–8 (2006).PubMedGoogle Scholar
  161. 161.
    Michelassi, F. et al. Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. Science 217, 841–3 (1982).PubMedCrossRefGoogle Scholar
  162. 162.
    Schellenberg, R.R. & Foster, A. Differential activity of leukotrienes upon human pulmonary vein and artery. Prostaglandins 27, 475–82 (1984).PubMedGoogle Scholar
  163. 163.
    Dahlen, S.E. et al. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci USA 78, 3887–91 (1981).PubMedCrossRefGoogle Scholar
  164. 164.
    Ciana, P. et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J 25, 4615–27 (2006).PubMedCrossRefGoogle Scholar
  165. 165.
    Hedlund, E., Gustafsson, J.A. & Warner, M. Cytochrome P450 in the brain; a review. Curr Drug Metab 2, 245–63 (2001).PubMedCrossRefGoogle Scholar
  166. 166.
    Strobel, H.W., Thompson, C.M. & Antonovic, L. Cytochromes P450 in brain: function and significance. Curr Drug Metab 2, 199–214 (2001).PubMedCrossRefGoogle Scholar
  167. 167.
    Peng, X., Zhang, C., Alkayed, N.J., Harder, D.R. & Koehler, R.C. Dependency of cortical functional hyperemia to forepaw stimulation on epoxygenase and nitric oxide synthase activities in rats. J Cereb Blood Flow Metab 24, 509–17 (2004).PubMedCrossRefGoogle Scholar
  168. 168.
    Michaelis, U.R., Falck, J.R., Schmidt, R., Busse, R. & Fleming, I. Cytochrome P4502C9-derived epoxyeicosatrienoic acids induce the expression of cyclooxygenase-2 in endothelial cells. Arterioscler Thromb Vasc Biol 25, 321–6 (2005).PubMedCrossRefGoogle Scholar
  169. 169.
    Munzenmaier, D.H. & Harder, D.R. Cerebral microvascular endothelial cell tube formation: role of astrocytic epoxyeicosatrienoic acid release. Am J Physiol Heart Circ Physiol 278, H1163–7 (2000).PubMedGoogle Scholar
  170. 170.
    Gebremedhin, D. et al. Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle. Am J Physiol 263, H519–25 (1992).PubMedGoogle Scholar
  171. 171.
    Alkayed, N.J. et al. Role of P-450 arachidonic acid epoxygenase in the response of cerebral blood flow to glutamate in rats. Stroke 28, 1066–72 (1997).PubMedCrossRefGoogle Scholar
  172. 172.
    Hardebo, J.E., Wieloch, T. & Kahrstrom, J. Excitatory amino acids and cerebrovascular tone. Acta Physiol Scand 136, 483–5 (1989).PubMedCrossRefGoogle Scholar
  173. 173.
    Takayasu, M. & Dacey, R.G., Jr. Effects of inhibitory and excitatory amino acid neurotransmitters on isolated cerebral parenchymal arterioles. Brain Res 482, 393–6 (1989).PubMedCrossRefGoogle Scholar
  174. 174.
    Alkayed, N.J. et al. Inhibition of brain P-450 arachidonic acid epoxygenase decreases baseline cerebral blood flow. Am J Physiol 271, H1541–6 (1996).PubMedGoogle Scholar
  175. 175.
    Kroetz, D.L. & Zeldin, D.C. Cytochrome P450 pathways of arachidonic acid metabolism. Curr Opin Lipidol 13, 273–83 (2002).PubMedCrossRefGoogle Scholar
  176. 176.
    Campbell, W.B. New role for epoxyeicosatrienoic acids as anti-inflammatory mediators. Trends Pharmacol Sci 21, 125–7 (2000).PubMedCrossRefGoogle Scholar
  177. 177.
    Node, K. et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285, 1276–9 (1999).PubMedCrossRefGoogle Scholar
  178. 178.
    Zeldin, D.C. & Liao, J.K. Reply: cytochrome P450-derived eicosanoids and the vascular wall. Trends Pharmacol Sci 21, 127–128 (2000).PubMedCrossRefGoogle Scholar
  179. 179.
    Koerner, I.P. et al. Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J Neurosci 27, 4642–9 (2007).PubMedCrossRefGoogle Scholar
  180. 180.
    Liu, M. & Alkayed, N.J. Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1alpha-linked induction of P450 2C11 epoxygenase in astrocytes. J Cereb Blood Flow Metab 25, 939–48 (2005).PubMedCrossRefGoogle Scholar
  181. 181.
    Zeldin, D.C. Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem 276, 36059–62 (2001).PubMedCrossRefGoogle Scholar
  182. 182.
    Spector, A.A. Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res 50 Suppl, S52–6 (2009).PubMedCrossRefGoogle Scholar
  183. 183.
    Kidd, P.M. Integrated brain restoration after ischemic stroke--medical management, risk factors, nutrients, and other interventions for managing inflammation and enhancing brain plasticity. Altern Med Rev 14, 14–35 (2009).PubMedGoogle Scholar
  184. 184.
    Lancelot, E., Callebert, J., Revaud, M.L., Boulu, R.G. & Plotkine, M. Detection of hydroxyl radicals in rat striatum during transient focal cerebral ischemia: possible implication in tissue damage. Neurosci Lett 197, 85–8 (1995).PubMedCrossRefGoogle Scholar
  185. 185.
    Negishi, H., Ikeda, K., Nara, Y. & Yamori, Y. Increased hydroxyl radicals in the hippocampus of stroke-prone spontaneously hypertensive rats during transient ischemia and recirculation. Neurosci Lett 306, 206–8 (2001).PubMedCrossRefGoogle Scholar
  186. 186.
    Gaetani, P. et al. Arachidonic acid metabolism and pathophysiologic aspects of subarachnoid hemorrhage in rats. Stroke 21, 328–32 (1990).PubMedCrossRefGoogle Scholar
  187. 187.
    Shohami, E., Rosenthal, J. & Lavy, S. The effect of incomplete cerebral ischemia on prostaglandin levels in rat brain. Stroke 13, 494–9 (1982).PubMedCrossRefGoogle Scholar
  188. 188.
    Gursoy-Ozdemir, Y., Can, A. & Dalkara, T. Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35, 1449–53 (2004).PubMedCrossRefGoogle Scholar
  189. 189.
    Gladstone, D.J., Black, S.E. & Hakim, A.M. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123–36 (2002).PubMedCrossRefGoogle Scholar
  190. 190.
    Badr, A.E., Yin, W., Mychaskiw, G. & Zhang, J.H. Dual effect of HBO on cerebral infarction in MCAO rats. Am J Physiol Regul Integr Comp Physiol 280, R766–70 (2001).PubMedGoogle Scholar
  191. 191.
    Lou, M., Eschenfelder, C.C., Herdegen, T., Brecht, S. & Deuschl, G. Therapeutic window for use of hyperbaric oxygenation in focal transient ischemia in rats. Stroke 35, 578–83 (2004).PubMedCrossRefGoogle Scholar
  192. 192.
    Rink, C. et al. Oxygen-sensitive outcomes and gene expression in acute ischemic stroke. J Cereb Blood Flow Metab.Google Scholar
  193. 193.
    Anderson, D.C. et al. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke 22, 1137–42 (1991).PubMedCrossRefGoogle Scholar
  194. 194.
    Nighoghossian, N., Trouillas, P., Adeleine, P. & Salord, F. Hyperbaric oxygen in the treatment of acute ischemic stroke. A double-blind pilot study. Stroke 26, 1369–72 (1995).Google Scholar
  195. 195.
    Rusyniak, D.E. et al. Hyperbaric oxygen therapy in acute ischemic stroke: results of the Hyperbaric Oxygen in Acute Ischemic Stroke Trial Pilot Study. Stroke 34, 571–4 (2003).PubMedCrossRefGoogle Scholar
  196. 196.
    Kim, G.W., Kondo, T., Noshita, N. & Chan, P.H. Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice: implications for the production and role of superoxide radicals. Stroke 33, 809–15 (2002).PubMedCrossRefGoogle Scholar
  197. 197.
    Sen, C.K., Khanna, S. & Roy, S. Tocotrienols in health and disease: the other half of the natural vitamin E family. Mol Aspects Med 28, 692–728 (2007).PubMedCrossRefGoogle Scholar
  198. 198.
    Khanna, S. et al. Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection. J Neurochem 112, 1249–60.Google Scholar
  199. 199.
    Khanna, S. et al. Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke 36, 2258–64 (2005).PubMedCrossRefGoogle Scholar
  200. 200.
    Khanna, S. et al. Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 278, 43508–15 (2003).PubMedCrossRefGoogle Scholar
  201. 201.
    Patel, V., Khanna, S., Roy, S., Ezziddin, O. & Sen, C.K. Natural vitamin E alpha-tocotrienol: retention in vital organs in response to long-term oral supplementation and withdrawal. Free Radic Res 40, 763–71 (2006).PubMedCrossRefGoogle Scholar
  202. 202.
    Khanna, S., Patel, V., Rink, C., Roy, S. & Sen, C.K. Delivery of orally supplemented alpha-tocotrienol to vital organs of rats and tocopherol-transport protein deficient mice. Free Radic Biol Med 39, 1310–9 (2005).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of SurgeryThe Ohio State University Medical CenterColumbusUSA

Personalised recommendations