Attenuation of postischemic brain hypoperfusion and reperfusion injury by the cyclooxygenase—lipoxygenase inhibitor BW755C

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✓ Arachidonic acid metabolites are believed to be important mediators of tissue injury during reperfusion after cerebral ischemia. To determine whether inhibiting the oxygen-dependent metabolism of arachidonic acid would reduce reperfusion injury, we administered the mixed cyclooxygenase—lipoxygenase inhibitor BW755C (3-amino-1-[m(trifluoromethyl) phenyl]-2-pyrazoline) near the time of reperfusion in a rat model of temporary focal ischemia. The duration of ischemia + reperfusion was 2 hours + 22 hours, 3 hours + 3 hours, or 3 hours + 21 hours. The effects of drug or saline treatment on infarct volume, blood-brain barrier permeability, and blood flow were determined. Cortical blood flow was monitored with laser Doppler flowmetry and blood-brain barrier permeability was evaluated by the Evans blue dye method. Infarct volume was determined in all groups by computerized image analysis of Nissl-stained sections. We found that BW755C treatment significantly attenuated delayed postischemic hypoperfusion in the 3 + 3 group (p < 0.05) and reduced the volume of Evans blue dye staining in the cortex (p < 0.01) and basal ganglia (p < 0.05). Hemispheric swelling was reduced in all treatment groups (p < 0.01), as was total infarct volume in the ischemic hemisphere (p < 0.05). These results support the hypothesis that arachidonic acid metabolites contribute to acute postischemic reperfusion injury and suggest that using a mixed cyclooxygenase—lipoxygenase inhibitor as an adjunct to thrombolytic or revascularization therapy could lengthen the ischemia time after which reperfusion is beneficial.

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Address reprint requests to: Philip R. Weinstein, M.D., Department of Neurological Surgery, The Editorial Office, 1360 Ninth Avenue, Suite 210, San Francisco, California 94122.
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References
  • 1.

    Ban MTonai TKohno Tet al: A flavonoid inhibitor of 5-lipoxygenase inhibits leukotriene production following ischemia in gerbil brain. Stroke 20:2482521989Ban M Tonai T Kohno T et al: A flavonoid inhibitor of 5-lipoxygenase inhibits leukotriene production following ischemia in gerbil brain. Stroke 20:248–252 1989

    • Search Google Scholar
    • Export Citation
  • 2.

    Bell BASymon LBranston NM: CBF and time thresholds for the formation of ischemic cerebral edema, and effect of reperfusion in baboons. J Neurosurg 62:31411985Bell BA Symon L Branston NM: CBF and time thresholds for the formation of ischemic cerebral edema and effect of reperfusion in baboons. J Neurosurg 62:31–41 1985

    • Search Google Scholar
    • Export Citation
  • 3.

    Bhakoo KKCrockard HALascelles PCet al: Prostaglandin synthesis and oedema formation during reperfusion following experimental brain ischemia in the gerbil. Stroke 15:8918951984Bhakoo KK Crockard HA Lascelles PC et al: Prostaglandin synthesis and oedema formation during reperfusion following experimental brain ischemia in the gerbil. Stroke 15:891–895 1984

    • Search Google Scholar
    • Export Citation
  • 4.

    Black KLHoff JT: Leukotrienes increase blood-brain barrier permeability following intraparenchymal injections in rats. Ann Neurol 18:3493511985Black KL Hoff JT: Leukotrienes increase blood-brain barrier permeability following intraparenchymal injections in rats. Ann Neurol 18:349–351 1985

    • Search Google Scholar
    • Export Citation
  • 5.

    Blackwell GJFlower RJ: 1-phenyl-3-pyrazolidone: an inhibitor of cyclo-oxygenase and lipoxygenase pathways in lung and platelets. Prostaglandins 16:4174251978Blackwell GJ Flower RJ: 1-phenyl-3-pyrazolidone: an inhibitor of cyclo-oxygenase and lipoxygenase pathways in lung and platelets. Prostaglandins 16:417–425 1978

    • Search Google Scholar
    • Export Citation
  • 6.

    Blasberg RGPatlak CSFenstermarcher JD: Selection of experimental conditions for the accurate determination of blood—brain transfer constants from single-time experiments: a theoretical analysis. J Cereb Blood Flow Metab 3:2152251983Blasberg RG Patlak CS Fenstermarcher JD: Selection of experimental conditions for the accurate determination of blood—brain transfer constants from single-time experiments: a theoretical analysis. J Cereb Blood Flow Metab 3:215–225 1983

    • Search Google Scholar
    • Export Citation
  • 7.

    Chan PHFishman RACaronna Jet al: Induction of brain edema following intracerebral injection of arachidonic acid. Ann Neurol 13:6256321983Chan PH Fishman RA Caronna J et al: Induction of brain edema following intracerebral injection of arachidonic acid. Ann Neurol 13:625–632 1983

    • Search Google Scholar
    • Export Citation
  • 8.

    Chen JGraham SHSimon RPet al: Extracellular glutamate and glucose utilization in caudate and cortex following focal ischemia and reperfusion in rats. Stroke 24:1771993 (Abstract)Chen J Graham SH Simon RP et al: Extracellular glutamate and glucose utilization in caudate and cortex following focal ischemia and reperfusion in rats. Stroke 24:177 1993 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 9.

    Chen JZarow GGraham Set al: Duration threshold of ischemia for early reperfusion injury in reversible focal ischemia model in rats. Stroke 22:1271991 (Abstract)Chen J Zarow G Graham S et al: Duration threshold of ischemia for early reperfusion injury in reversible focal ischemia model in rats. Stroke 22:127 1991 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 10.

    Cole DJPatel PMSchell RMet al: Brain eicosanoid levels during temporary focal cerebral ischemia in rats: a microdialysis study. J Neurosurg Anesthesiol 5:41471993Cole DJ Patel PM Schell RM et al: Brain eicosanoid levels during temporary focal cerebral ischemia in rats: a microdialysis study. J Neurosurg Anesthesiol 5:41–47 1993

    • Search Google Scholar
    • Export Citation
  • 11.

    Crowell RMOlsson YKlatzo Iet al: Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke 1:4394481970Crowell RM Olsson Y Klatzo I et al: Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke 1:439–448 1970

    • Search Google Scholar
    • Export Citation
  • 12.

    Dempsey RJRoy MWMeyer Ket al: Development of cyclooxygenase and lipoxygenase metabolites of arachidonic acid after transient cerebral ischemia. J Neurosurg 64:1181241986Dempsey RJ Roy MW Meyer K et al: Development of cyclooxygenase and lipoxygenase metabolites of arachidonic acid after transient cerebral ischemia. J Neurosurg 64:118–124 1986

    • Search Google Scholar
    • Export Citation
  • 13.

    Dietrich WDBusto RAlonso Oet al: Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 13:5415491993Dietrich WD Busto R Alonso O et al: Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 13:541–549 1993

    • Search Google Scholar
    • Export Citation
  • 14.

    Dirnagl UKaplan BJacewicz Met al: Continuous measurement of cerebral cortical blood flow by laser—Doppler flowmetry in a rat stroke model. J Cereb Blood Flow Metab 9:5895961989Dirnagl U Kaplan B Jacewicz M et al: Continuous measurement of cerebral cortical blood flow by laser—Doppler flowmetry in a rat stroke model. J Cereb Blood Flow Metab 9:589–596 1989

    • Search Google Scholar
    • Export Citation
  • 15.

    Dumuis APin JPOomagari Ket al: Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature 347:1821841990Dumuis A Pin JP Oomagari K et al: Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature 347:182–184 1990

    • Search Google Scholar
    • Export Citation
  • 16.

    Faden AILemke MDemediuk P: Effects of BW755C, a mixed cyclooxygenase—lipoxygenase inhibitor, following traumatic spinal cord injury in rats. Brain Res 463:63681988Faden AI Lemke M Demediuk P: Effects of BW755C a mixed cyclooxygenase—lipoxygenase inhibitor following traumatic spinal cord injury in rats. Brain Res 463:63–68 1988

    • Search Google Scholar
    • Export Citation
  • 17.

    Faden AIWeinstein PBakshi Ret al: Biochemical changes and secondary tissue injury after brain and spinal cord ischemia in Bazan NGBraquet PGinzberg MD (eds): Neurochemical Correlates of Cerebral Ischemia. New York: Plenum1992 pp 161181Faden AI Weinstein P Bakshi R et al: Biochemical changes and secondary tissue injury after brain and spinal cord ischemia in Bazan NG Braquet P Ginzberg MD (eds): Neurochemical Correlates of Cerebral Ischemia. New York: Plenum 1992 pp 161–181

    • Search Google Scholar
    • Export Citation
  • 18.

    Graham SHChen J: Role of lipoxygenase products in postischemic hypoperfusion. Neurology (Suppl) 42:1661992 (Abstract)Graham SH Chen J: Role of lipoxygenase products in postischemic hypoperfusion. Neurology (Suppl) 42:166 1992 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 19.

    Hallenbeck JMDutka AJTanishma Tet al: Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 17:2462531986Hallenbeck JM Dutka AJ Tanishma T et al: Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 17:246–253 1986

    • Search Google Scholar
    • Export Citation
  • 20.

    Higgs GAMugridge KGMoncada Set al: Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C. Proc Natl Acad Sci USA 81:289028921984Higgs GA Mugridge KG Moncada S et al: Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C. Proc Natl Acad Sci USA 81:2890–2892 1984

    • Search Google Scholar
    • Export Citation
  • 21.

    Iannotti FHoff J: Ischemic brain edema with and without reperfusion: an experimental study in gerbils. Stroke 14:5625671983Iannotti F Hoff J: Ischemic brain edema with and without reperfusion: an experimental study in gerbils. Stroke 14:562–567 1983

    • Search Google Scholar
    • Export Citation
  • 22.

    Laha RKIsraeli JDujovny M: Low molecular weight dextran in experimental embolectomy. Stroke 11:59631980Laha RK Israeli J Dujovny M: Low molecular weight dextran in experimental embolectomy. Stroke 11:59–63 1980

    • Search Google Scholar
    • Export Citation
  • 23.

    Lang SAMaron MB: Role of prostaglandins in blood-induced vasoconstriction of canine cerebral arteries. J Cereb Blood Flow Metab 8:1091151988Lang SA Maron MB: Role of prostaglandins in blood-induced vasoconstriction of canine cerebral arteries. J Cereb Blood Flow Metab 8:109–115 1988

    • Search Google Scholar
    • Export Citation
  • 24.

    Lin TNHe YYWu Get al: Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24:1171211993Lin TN He YY Wu G et al: Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24:117–121 1993

    • Search Google Scholar
    • Export Citation
  • 25.

    Miyasaka KMikami T: Comparison of the anti-inflammatory effects of dexamethasone, indomethacin and BW755C on carrageenin-induced pleurisy in rats. Eur J Pharmacol 77:2292361982Miyasaka K Mikami T: Comparison of the anti-inflammatory effects of dexamethasone indomethacin and BW755C on carrageenin-induced pleurisy in rats. Eur J Pharmacol 77:229–236 1982

    • Search Google Scholar
    • Export Citation
  • 26.

    Moncada SVane JR: Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med 300:114211471979Moncada S Vane JR: Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med 300:1142–1147 1979

    • Search Google Scholar
    • Export Citation
  • 27.

    Moskowitz MAKiwak KJHekimian Ket al: Synthesis of compounds with properties of leukotrienes C4 and D4 in gerbil brains after ischemia and reperfusion. Science 224:8868891984Moskowitz MA Kiwak KJ Hekimian K et al: Synthesis of compounds with properties of leukotrienes C4 and D4 in gerbil brains after ischemia and reperfusion. Science 224:886–889 1984

    • Search Google Scholar
    • Export Citation
  • 28.

    Mullane KMMoncada S: The salvage of ischaemic myocardium by BW755C in anaesthetised dogs. Prostaglandins 24:2552661982Mullane KM Moncada S: The salvage of ischaemic myocardium by BW755C in anaesthetised dogs. Prostaglandins 24:255–266 1982

    • Search Google Scholar
    • Export Citation
  • 29.

    Murphy TParikh ASchnaar Ret al: Arachidonic acid metabolism in glutamate neurotoxicity. Ann NY Acad Sci 559:4744771989Murphy T Parikh A Schnaar R et al: Arachidonic acid metabolism in glutamate neurotoxicity. Ann NY Acad Sci 559:474–477 1989

    • Search Google Scholar
    • Export Citation
  • 30.

    Nakagomi TSasaki TKirino Tet al: Effect of cyclooxygenase and lipoxygenase inhibitors on delayed neuronal death in the gerbil hippocampus. Stroke 20:9259291989Nakagomi T Sasaki T Kirino T et al: Effect of cyclooxygenase and lipoxygenase inhibitors on delayed neuronal death in the gerbil hippocampus. Stroke 20:925–929 1989

    • Search Google Scholar
    • Export Citation
  • 31.

    Palmblad JMalmsten CLUdén AMet al: Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence. Blood 58:6586611981Palmblad J Malmsten CL Udén AM et al: Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence. Blood 58:658–661 1981

    • Search Google Scholar
    • Export Citation
  • 32.

    Palmer MRMathews RMurphy RCet al: Leukotriene C elicits a prolonged excitation of cerebellar Purkinje neurons. Neurosci Lett 18:1731801980Palmer MR Mathews R Murphy RC et al: Leukotriene C elicits a prolonged excitation of cerebellar Purkinje neurons. Neurosci Lett 18:173–180 1980

    • Search Google Scholar
    • Export Citation
  • 33.

    Patterson RPruzansky JJHarris KE: An agent that releases basophil and mast cell histamine but blocks cyclooxygenase and lipoxygenase metabolism of arachidonic acid inhibits immunoglobulin E-mediated asthma in rhesus monkeys. J Allergy Clin Immunol 67:4444491981Patterson R Pruzansky JJ Harris KE: An agent that releases basophil and mast cell histamine but blocks cyclooxygenase and lipoxygenase metabolism of arachidonic acid inhibits immunoglobulin E-mediated asthma in rhesus monkeys. J Allergy Clin Immunol 67:444–449 1981

    • Search Google Scholar
    • Export Citation
  • 34.

    Piomelli DShapiro EFeinmark SJet al: Metabolites of arachidonic acid in the nervous system of Aplysia: possible mediators of synaptic modulation. J Neurosci 7:367536861987Piomelli D Shapiro E Feinmark SJ et al: Metabolites of arachidonic acid in the nervous system of Aplysia: possible mediators of synaptic modulation. J Neurosci 7:3675–3686 1987

    • Search Google Scholar
    • Export Citation
  • 35.

    Piomelli DVolterra ADale Net al: Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 328:38431987Piomelli D Volterra A Dale N et al: Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 328:38–43 1987

    • Search Google Scholar
    • Export Citation
  • 36.

    Rosenblum WI: Constricting effect of leukotrienes on cerebral arterioles of mice. Stroke 16:2622631985Rosenblum WI: Constricting effect of leukotrienes on cerebral arterioles of mice. Stroke 16:262–263 1985

    • Search Google Scholar
    • Export Citation
  • 37.

    Salmon JASimmons PMMoncada S: The effects of BW755C and other anti-inflammatory drugs on eicosanoid concentrations and leukocyte accumulation in experimentally-induced acute inflammation. J Pharm Pharmacol 35:8088131983Salmon JA Simmons PM Moncada S: The effects of BW755C and other anti-inflammatory drugs on eicosanoid concentrations and leukocyte accumulation in experimentally-induced acute inflammation. J Pharm Pharmacol 35:808–813 1983

    • Search Google Scholar
    • Export Citation
  • 38.

    Shappell SBTaylor AAHughes Het al: Comparison of antioxidant and nonantioxidant lipoxygenase inhibitors on neutrophil function. Implications for pathogenesis of myocardial reperfusion injury. J Pharmacol Exp Ther 252:5315381990Shappell SB Taylor AA Hughes H et al: Comparison of antioxidant and nonantioxidant lipoxygenase inhibitors on neutrophil function. Implications for pathogenesis of myocardial reperfusion injury. J Pharmacol Exp Ther 252:531–538 1990

    • Search Google Scholar
    • Export Citation
  • 39.

    Shigeno TTeasdale GMMcCulloch Jet al: Recirculation model following MCA occlusion in rats. Cerebral blood flow, cerebrovascular permeability, and brain edema. J Neurosurg 63:2722771985Shigeno T Teasdale GM McCulloch J et al: Recirculation model following MCA occlusion in rats. Cerebral blood flow cerebrovascular permeability and brain edema. J Neurosurg 63:272–277 1985

    • Search Google Scholar
    • Export Citation
  • 40.

    Skarphedinsson JOHårding HThorén P: Repeated measurements of cerebral blood flow in rats. Comparisons between the hydrogen clearance method and laser Doppler flowmetry. Acta Physiol Scand 134:1331421988Skarphedinsson JO Hårding H Thorén P: Repeated measurements of cerebral blood flow in rats. Comparisons between the hydrogen clearance method and laser Doppler flowmetry. Acta Physiol Scand 134:133–142 1988

    • Search Google Scholar
    • Export Citation
  • 41.

    Swanson RAMorton MTTsao-Wu Get al: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:2902931990Swanson RA Morton MT Tsao-Wu G et al: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290–293 1990

    • Search Google Scholar
    • Export Citation
  • 42.

    Tagari PDu Boulay GHAitken Vet al: Leukotriene D4 and the cerebral vasculature in vivo and in vitro. Prostaglandins Leukotriene Med 11:2812971983Tagari P Du Boulay GH Aitken V et al: Leukotriene D4 and the cerebral vasculature in vivo and in vitro. Prostaglandins Leukotriene Med 11:281–297 1983

    • Search Google Scholar
    • Export Citation
  • 43.

    Usui MAsano TTakakura K: Identification and quantitative analysis of hydroxy-eicosatetraenoic acids in rat brains exposed to regional ischemia. Stroke 18:4904941987Usui M Asano T Takakura K: Identification and quantitative analysis of hydroxy-eicosatetraenoic acids in rat brains exposed to regional ischemia. Stroke 18:490–494 1987

    • Search Google Scholar
    • Export Citation
  • 44.

    Williams JHBliss TVP: Induction but not maintenance of calcium-induced long-term potentiation in dentate gyrus and area CA1 of the hippocampal slice is blocked by nordihydroguaiaretic acid. Neurosci Lett 88:81851988Williams JH Bliss TVP: Induction but not maintenance of calcium-induced long-term potentiation in dentate gyrus and area CA1 of the hippocampal slice is blocked by nordihydroguaiaretic acid. Neurosci Lett 88:81–85 1988

    • Search Google Scholar
    • Export Citation
  • 45.

    Wolfe LSCoceani F: The role of prostaglandins in the central nervous system. Annu Rev Physiol 41:6696841979Wolfe LS Coceani F: The role of prostaglandins in the central nervous system. Annu Rev Physiol 41:669–684 1979

    • Search Google Scholar
    • Export Citation
  • 46.

    Yokota MTani EMaeda Yet al: Effect of 5-lipoxygenase inhibitor on experimental delayed cerebral vasospasm. Stroke 18:5125181987Yokota M Tani E Maeda Y et al: Effect of 5-lipoxygenase inhibitor on experimental delayed cerebral vasospasm. Stroke 18:512–518 1987

    • Search Google Scholar
    • Export Citation
  • 47.

    Yoshida SIkeda MBusto R: Cerebral phosphoinositide, triacylglycerol, and energy metabolism in reversible ischemia: origin and fate of free fatty acids. J Neurochem 47:7447571986Yoshida S Ikeda M Busto R: Cerebral phosphoinositide triacylglycerol and energy metabolism in reversible ischemia: origin and fate of free fatty acids. J Neurochem 47:744–757 1986

    • Search Google Scholar
    • Export Citation
  • 48.

    Zea Longa EWeinstein PRCarlson Set al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84911989Zea Longa E Weinstein PR Carlson S et al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91 1989

    • Search Google Scholar
    • Export Citation
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