Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats

Candelario-Jalil, Eduardo and Gonzalez-Falcon, Armando and Garcia-Cabrera, Michel and Leon, Olga Sonia and Fiebich, Bernd (2007) Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. [Journal (Paginated)]

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Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E2 (PGE2) levels, myeloperoxidase (MPO) activity, Evans Blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischemia in the rat. Postischemic treatment with nimesulide markedly reduced the increase in PGE2 levels in the ischemic cerebral cortex 24 h after stroke and diminished infarct size by 48 % with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the other hand, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition.

Item Type:Journal (Paginated)
Keywords:Cyclooxygenase; prostaglandin E2; stroke; blood-brain barrier; leukocyte infiltration; cerebral ischemia; vasogenic edema; cerebral infarct; neuroprotection; prostanoids; COX-2; COX-1; neurodegeneration
Subjects:Neuroscience > Neurochemistry
ID Code:5393
Deposited By: Candelario-Jalil, Dr Eduardo
Deposited On:19 Feb 2007
Last Modified:11 Mar 2011 08:56

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Abbott N. J. (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol. Neurobiol. 20, 131-147.

Adams J., Collaco-Moraes Y. and de B. J. (1996) Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation. J. Neurochem. 66, 6-13.

Akundi R. S., Candelario-Jalil E., Hess S., Hull M., Lieb K., Gebicke-Haerter P. J. and Fiebich B. L. (2005) Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia. Glia 51, 199-208.

Asahi M., Wang X., Mori T., Sumii T., Jung J. C., Moskowitz M. A., Fini M. E. and Lo E. H. (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724-7732.

Baird A. E., Benfield A., Schlaug G., Siewert B., Lovblad K. O., Edelman R. R. and Warach S. (1997) Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging. Ann. Neurol. 41, 581-589.

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

Barone F. C. and Feuerstein G. Z. (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J. Cereb. Blood Flow Metab 19, 819-834.

Batteur-Parmentier S., Margaill I. and Plotkine M. (2000) Modulation by nitric oxide of cerebral neutrophil accumulation after transient focal ischemia in rats. J. Cereb. Blood Flow Metab 20, 812-819.

Belayev L., Busto R., Ikeda M., Rubin L. L., Kajiwara A., Morgan L. and Ginsberg M. D. (1998) Protection against blood-brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study. Brain Res. 787, 277-285.

Belayev L., Busto R., Zhao W. and Ginsberg M. D. (1996) Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 739, 88-96.

Biagas K. V., Uhl M. W., Schiding J. K., Nemoto E. M. and Kochanek P. M. (1992) Assessment of posttraumatic polymorphonuclear leukocyte accumulation in rat brain using tissue myeloperoxidase assay and vinblastine treatment. J. Neurotrauma 9, 363-371.

Candelario-Jalil E., Akundi R. S., Bhatia H. S., Lieb K., Appel K., Munoz E., Hull M. and Fiebich B. L. (2006) Ascorbic acid enhances the inhibitory effect of aspirin on neuronal cyclooxygenase-2-mediated prostaglandin E(2) production. J. Neuroimmunol. 174, 39-51.

Candelario-Jalil E., Alvarez D., Gonzalez-Falcon A., Garcia-Cabrera M., Martinez-Sanchez G., Merino N., Giuliani A. and Leon O. S. (2002) Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia. Eur. J. Pharmacol. 453, 189-195.

Candelario-Jalil E., Alvarez D., Merino N. and Leon O. S. (2003a) Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils. Neurosci. Res. 47, 245-253.

Candelario-Jalil E., Gonzalez-Falcon A., Garcia-Cabrera M., Alvarez D., Al-Dalain S., Martinez G., Leon O. S. and Springer J. E. (2003b) Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J. Neurochem. 86, 545-555.

Candelario-Jalil E., Gonzalez-Falcon A., Garcia-Cabrera M., Leon O. S. and Fiebich B. L. (2004) Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat. Brain Res. 1007, 98-108.

Candelario-Jalil E., Mhadu N. H., Gonzalez-Falcon A., Garcia-Cabrera M., Munoz E., Leon O. S. and Fiebich B. L. (2005) Effects of the cyclooxygenase-2 inhibitor nimesulide on cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion in the rat. J. Neuroinflammation. 2, 3.

Chandrasekharan N. V., Dai H., Roos K. L., Evanson N. K., Tomsik J., Elton T. S. and Simmons D. L. (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. U. S. A 99, 13926-13931.

Chen J., Weinstein P. R. and Graham S. H. (1995) Attenuation of postischemic brain hypoperfusion and reperfusion injury by the cyclooxygenase-lipoxygenase inhibitor BW755C. J. Neurosurg. 83, 99-104.

Cheung R. T., Pei Z., Feng Z. H. and Zou L. Y. (2002) Cyclooxygenase-1 gene knockout does not alter middle cerebral artery occlusion in a mouse stroke model. Neurosci. Lett. 330, 57-60.

Cipollone F., Fazia M. L., Iezzi A., Cuccurullo C., De C. D., Ucchino S., Spigonardo F., Marchetti A., Buttitta F., Paloscia L., Mascellanti M., Cuccurullo F. and Mezzetti A. (2005) Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human. Arterioscler. Thromb. Vasc. Biol. 25, 1925-1931.

Clark W. M., Wissman S., Albers G. W., Jhamandas J. H., Madden K. P. and Hamilton S. (1999) Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 282, 2019-2026.

Collaco-Moraes Y., Aspey B., Harrison M. and de B. J. (1996) Cyclo-oxygenase-2 messenger RNA induction in focal cerebral ischemia. J. Cereb. Blood Flow Metab 16, 1366-1372.

Couturier J. Y., ng-Zhou L., Croci N., Plotkine M. and Margaill I. (2003) 3-Aminobenzamide reduces brain infarction and neutrophil infiltration after transient focal cerebral ischemia in mice. Exp. Neurol. 184, 973-980.

Davis S., Lees K. and Donnan G. (2006) Treating the acute stroke patient as an emergency: current practices and future opportunities. Int. J. Clin. Pract. 60, 399-407.

Ding-Zhou L., Marchand-Verrecchia C., Palmier B., Croci N., Chabrier P. E., Plotkine M. and Margaill I. (2003) Neuroprotective effects of (S)-N-[4-[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2- yl)carbonyl]-1-piperazinyl]phenyl]-2-thiophenecarboximid-amide (BN 80933), an inhibitor of neuronal nitric-oxide synthase and an antioxidant, in model of transient focal cerebral ischemia in mice. J. Pharmacol. Exp. Ther. 306, 588-594.

Dirnagl U. (2004) Inflammation in stroke: the good, the bad, and the unknown. Ernst. Schering. Res. Found. Workshop 87-99.

Dirnagl U., Iadecola C. and Moskowitz M. A. (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391-397.

Famaey J. P. (1997) In vitro and in vivo pharmacological evidence of selective cyclooxygenase-2 inhibition by nimesulide: an overview. Inflamm. Res. 46, 437-446.

Fisher M. (1997) Characterizing the target of acute stroke therapy. Stroke 28, 866-872.

Gonzalez-Falcon A., Candelario-Jalil E., Garcia-Cabrera M. and Leon O. S. (2003) Effects of pyruvate administration on infarct volume and neurological deficits following permanent focal cerebral ischemia in rats. Brain Res. 990, 1-7.

Gopez J. J., Yue H., Vasudevan R., Malik A. S., Fogelsanger L. N., Lewis S., Panikashvili D., Shohami E., Jansen S. A., Narayan R. K. and Strauss K. I. (2005) Cyclooxygenase-2-specific inhibitor improves functional outcomes, provides neuroprotection, and reduces inflammation in a rat model of traumatic brain injury. Neurosurgery 56, 590-604.

Hacke W., Schwab S., Horn M., Spranger M., De G. M. and von K. R. (1996) 'Malignant' middle cerebral artery territory infarction: clinical course and prognostic signs. Arch. Neurol. 53, 309-315.

Hartl R., Schurer L., Schmid-Schonbein G. W. and del Zoppo G. J. (1996) Experimental antileukocyte interventions in cerebral ischemia. J. Cereb. Blood Flow Metab 16, 1108-1119.

Hawkins B. T. and Davis T. P. (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173-185.

Heo J. H., Han S. W. and Lee S. K. (2005) Free radicals as triggers of brain edema formation after stroke. Free Radic. Biol. Med. 39, 51-70.

Hewett S. J., Bell S. C. and Hewett J. A. (2006) Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the central nervous system. Pharmacol. Ther. 112, 335-357.

Hewett S. J., Uliasz T. F., Vidwans A. S. and Hewett J. A. (2000) Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. J. Pharmacol. Exp. Ther. 293, 417-425.

Huang Z. G., Xue D., Preston E., Karbalai H. and Buchan A. M. (1999) Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can. J. Neurol. Sci. 26, 298-304.

Iadecola C., Niwa K., Nogawa S., Zhao X., Nagayama M., Araki E., Morham S. and Ross M. E. (2001a) Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc. Natl. Acad. Sci. U. S. A 98, 1294-1299.

Iadecola C. and Ross M. E. (1997) Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection. Ann. N. Y. Acad. Sci. 835, 203-217.

Iadecola C., Sugimoto K., Niwa K., Kazama K. and Ross M. E. (2001b) Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice. J. Cereb. Blood Flow Metab 21, 1436-1441.

Ikeda-Matsuo Y., Ota A., Fukada T., Uematsu S., Akira S. and Sasaki Y. (2006) Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury. Proc. Natl. Acad. Sci. U. S. A 103, 11790-11795.

Im J. Y., Kim D., Paik S. G. and Han P. L. (2006) Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. Free Radic. Biol. Med. 41, 960-972.

Kawaguchi K., Hickey R. W., Rose M. E., Zhu L., Chen J. and Graham S. H. (2005) Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res. 1050, 130-137.

Kawano T., Anrather J., Zhou P., Park L., Wang G., Frys K. A., Kunz A., Cho S., Orio M. and Iadecola C. (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat. Med. 12, 225-229.

Khan K. M., Howe L. R. and Falcone D. J. (2004) Extracellular matrix-induced cyclooxygenase-2 regulates macrophage proteinase expression. J. Biol. Chem. 279, 22039-22046.

Koizumi J., Yoshida Y., Nakazawa T. and Ooneda G. (1986) Experimental studies of ischemic brain edema. 1. 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.

Kondo T., Reaume A. G., Huang T. T., Carlson E., Murakami K., Chen S. F., Hoffman E. K., Scott R. W., Epstein C. J. and Chan P. H. (1997) Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17, 4180-4189.

Krizanac-Bengez L., Mayberg M. R., Cunningham E., Hossain M., Ponnampalam S., Parkinson F. E. and Janigro D. (2006) Loss of shear stress induces leukocyte-mediated cytokine release and blood-brain barrier failure in dynamic in vitro blood-brain barrier model. J. Cell Physiol 206, 68-77.

Longa E. Z., Weinstein P. R., Carlson S. and Cummins R. (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84-91.

Marchal G., Beaudouin V., Rioux P., de l. S., V, Le D. F., Viader F., Derlon J. M. and Baron J. C. (1996) Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke 27, 599-606.

Mark K. S., Trickler W. J. and Miller D. W. (2001) Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J. Pharmacol. Exp. Ther. 297, 1051-1058.

Martin A., Rojas S., Chamorro A., Falcon C., Bargallo N. and Planas A. M. (2006) Why does acute hyperglycemia worsen the outcome of transient focal cerebral ischemia? Role of corticosteroids, inflammation, and protein O-glycosylation. Stroke 37, 1288-1295.

Matsuo Y., Mihara S., Ninomiya M. and Fujimoto M. (2001) Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats. Stroke 32, 2143-2148.

Miettinen S., Fusco F. R., Yrjanheikki J., Keinanen R., Hirvonen T., Roivainen R., Narhi M., Hokfelt T. and Koistinaho J. (1997) 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. U. S. A 94, 6500-6505.

Minematsu K., Li L., Sotak C. H., Davis M. A. and Fisher M. (1992) Reversible focal ischemic injury demonstrated by diffusion-weighted magnetic resonance imaging in rats. Stroke 23, 1304-1310.

Muralikrishna A. R. and Hatcher J. F. (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic. Biol. Med. 40, 376-387.

Nagayama M., Niwa K., Nagayama T., Ross M. E. and Iadecola C. (1999) The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene. J. Cereb. Blood Flow Metab 19, 1213-1219.

Nogawa S., Forster C., Zhang F., Nagayama M., Ross M. E. and Iadecola C. (1998) Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc. Natl. Acad. Sci. U. S. A 95, 10966-10971.

Nogawa S., Zhang F., Ross M. E. and Iadecola C. (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J. Neurosci. 17, 2746-2755.

Pavlovic S., Du B., Sakamoto K., Khan K. M., Natarajan C., Breyer R. M., Dannenberg A. J. and Falcone D. J. (2006) Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages. J. Biol. Chem. 281, 3321-3328.

Pepicelli O., Fedele E., Berardi M., Raiteri M., Levi G., Greco A., Ajmone-Cat M. A. and Minghetti L. (2005) Cyclo-oxygenase-1 and -2 differently contribute to prostaglandin E2 synthesis and lipid peroxidation after in vivo activation of N-methyl-D-aspartate receptors in rat hippocampus. J. Neurochem. 93, 1561-1567.

Pepicelli O., Fedele E., Bonanno G., Raiteri M., Ajmone-Cat M. A., Greco A., Levi G. and Minghetti L. (2002) In vivo activation of N-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E(2) extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms. J. Neurochem. 81, 1028-1034.

Phillis J. W. and O'Regan M. H. (2003) The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries. Crit Rev. Neurobiol. 15, 61-90.

Phillis J. W. and O'Regan M. H. (2004) A potentially critical role of phospholipases in central nervous system ischemic, traumatic, and neurodegenerative disorders. Brain Res. Brain Res. Rev. 44, 13-47.

Planas A. M., Soriano M. A., Justicia C. and Rodriguez-Farre E. (1999) Induction of cyclooxygenase-2 in the rat brain after a mild episode of focal ischemia without tissue inflammation or neural cell damage. Neurosci. Lett. 275, 141-144.

Planas A. M., Soriano M. A., Rodriguez-Farre E. and Ferrer I. (1995) Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain. Neurosci. Lett. 200, 187-190.

Powell W. S. (1982) Rapid extraction of arachidonic acid metabolites from biological samples using octadecylsilyl silica. Methods Enzymol. 86, 467-477.

Reglodi D., Somogyvari-Vigh A., Vigh S., Kozicz T. and Arimura A. (2000) Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat. Stroke 31, 1411-1417.

Rosenberg G. A. (1999) Ischemic brain edema. Prog. Cardiovasc. Dis. 42, 209-216.

Rosenberg G. A., Estrada E. Y. and Dencoff J. E. (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29, 2189-2195.

Rosenberg G. A., Navratil M., Barone F. and Feuerstein G. (1996) Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J. Cereb. Blood Flow Metab 16, 360-366.

Salzberg-Brenhouse H. C., Chen E. Y., Emerich D. F., Baldwin S., Hogeland K., Ranelli S., Lafreniere D., Perdomo B., Novak L., Kladis T., Fu K., Basile A. S., Kordower J. H. and Bartus R. T. (2003) Inhibitors of cyclooxygenase-2, but not cyclooxygenase-1 provide structural and functional protection against quinolinic acid-induced neurodegeneration. J. Pharmacol. Exp. Ther. 306, 218-228.

Sasaki T., Kitagawa K., Yamagata K., Takemiya T., Tanaka S., Omura-Matsuoka E., Sugiura S., Matsumoto M. and Hori M. (2004) Amelioration of hippocampal neuronal damage after transient forebrain ischemia in cyclooxygenase-2-deficient mice. J. Cereb. Blood Flow Metab 24, 107-113.

Scali C., Prosperi C., Vannucchi M. G., Pepeu G. and Casamenti F. (2000) Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer's disease. Eur. J. Neurosci. 12, 1900-1912.

Smith W. L., DeWitt D. L. and Garavito R. M. (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145-182.

Snipes J. A., Kis B., Shelness G. S., Hewett J. A. and Busija D. W. (2005) Cloning and characterization of cyclooxygenase-1b (putative cyclooxygenase-3) in rat. J. Pharmacol. Exp. Ther. 313, 668-676.

Stanimirovic D. and Satoh K. (2000) Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 10, 113-126.

Stanimirovic D., Shapiro A., Wong J., Hutchison J. and Durkin J. (1997) The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion. J. Neuroimmunol. 76, 193-205.

Strauss K. I., Barbe M. F., Marshall R. M., Raghupathi R., Mehta S. and Narayan R. K. (2000) Prolonged cyclooxygenase-2 induction in neurons and glia following traumatic brain injury in the rat. J. Neurotrauma 17, 695-711.

Sugimoto K. and Iadecola C. (2003) Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res. 960, 273-276.

Taylor T. N., Davis P. H., Torner J. C., Holmes J., Meyer J. W. and Jacobson M. F. (1996) Lifetime cost of stroke in the United States. Stroke 27, 1459-1466.

Toutain P. L., Cester C. C., Haak T. and Metge S. (2001) Pharmacokinetic profile and in vitro selective cyclooxygenase-2 inhibition by nimesulide in the dog. J. Vet. Pharmacol. Ther. 24, 35-42.

Tyurin V. A., Tyurina Y. Y., Borisenko G. G., Sokolova T. V., Ritov V. B., Quinn P. J., Rose M., Kochanek P., Graham S. H. and Kagan V. E. (2000) Oxidative stress following traumatic brain injury in rats: quantitation of biomarkers and detection of free radical intermediates. J. Neurochem. 75, 2178-2189.

Wahl M., Unterberg A., Baethmann A. and Schilling L. (1988) Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. J. Cereb. Blood Flow Metab 8, 621-634.

Yamagata K., Andreasson K. I., Kaufmann W. E., Barnes C. A. and Worley P. F. (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11, 371-386.

Yang Y., Li Q., Miyashita H., Howlett W., Siddiqui M. and Shuaib A. (2000) Usefulness of postischemic thrombolysis with or without neuroprotection in a focal embolic model of cerebral ischemia. J. Neurosurg. 92, 841-847.

Yang Y., Shuaib A. and Li Q. (1998) Quantification of infarct size on focal cerebral ischemia model of rats using a simple and economical method. J. Neurosci. Methods 84, 9-16.


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