--- abstract: 'Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3 to 24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E2 (PGE2) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE2 accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage. ' altloc: [] chapter: ~ commentary: ~ commref: ~ confdates: ~ conference: ~ confloc: ~ contact_email: ~ creators_id: [] creators_name: - family: Candelario-Jalil given: Eduardo honourific: '' lineage: '' - family: González-Falcón given: Armando honourific: '' lineage: '' - family: García-Cabrera given: Michel honourific: '' lineage: '' - family: León given: Olga S. honourific: '' lineage: '' - family: Fiebich given: Bernd L. honourific: '' lineage: '' date: 2004-05 date_type: published datestamp: 2007-07-28 department: ~ dir: disk0/00/00/56/17 edit_lock_since: ~ edit_lock_until: ~ edit_lock_user: ~ editors_id: [] editors_name: - family: Bloom given: Floyd honourific: '' lineage: '' eprint_status: archive eprintid: 5617 fileinfo: /style/images/fileicons/application_pdf.png;/5617/1/Brain_Res_2004_nimesulide_stroke.pdf full_text_status: public importid: ~ institution: ~ isbn: ~ ispublished: pub issn: ~ item_issues_comment: [] item_issues_count: 0 item_issues_description: [] item_issues_id: [] item_issues_reported_by: [] item_issues_resolved_by: [] item_issues_status: [] item_issues_timestamp: [] item_issues_type: [] keywords: cerebral ischemia; nimesulide; cyclooxygenase-2; functional outcome; stroke; neuroprotection lastmod: 2011-03-11 08:56:54 latitude: ~ longitude: ~ metadata_visibility: show note: ~ number: 1-2 pagerange: 98-108 pubdom: FALSE publication: Brain Research publisher: Elsevier refereed: TRUE referencetext: | [1] K. Abe, Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury, J. Cereb. Blood Flow Metab. 20 (2000) 1393-1408. [2] G. W. Albers, Expanding the Window for Thrombolytic Therapy in Acute Stroke, Stroke 30 (1999) 2230-2237. [3] A. Azab, V. Fraifeld, J. Kaplanski, Nimesulide prevents lipopolysaccharide-induced elevation in plasma tumor necrosis factor-alpha in rats, Life Sci. 63 (1998) 323-327. [4] F.C. Barone, G.Z. Feuerstein, Inflammatory mediators and stroke: new opportunities for novel therapeutics, J. Cereb. Blood Flow Metab. 19 (1999) 819-834. [5] C.D. Breder, D. Dewitt, R.P. Kraig, Characterization of inducible cyclooxygenase in rat brain, J. Comp. Neurol. 355 (1995) 296-315. [6] J.K. Callaway, M.J. Knight, D.J. Watkins, P.M. Beart, B. Jarrott, Delayed treatment with AM-36, a novel neuroprotective agent, reduces neuronal damage after endothelin-1-induced middle cerebral artery occlusion in conscious rats, Stroke 30 (1999) 2704–2712. [7] J.K. Callaway, A.J. Lawrence, B. Jarrott, AM-36, a novel neuroprotective agent, profoundly reduces reactive oxygen species formation and dopamine release in the striatum of conscious rats after endothelin-1-induced middle cerebral artery occlusion, Neuropharmacology 44 (2003) 787–800. [8] E. Candelario-Jalil, H.H. Ajamieh, S. Sam, G. Martínez, O.S. León, Nimesulide limits kainate-induced oxidative damage in the rat hippocampus, Eur. J. Pharmacol. 390 (2000) 295-298. [9] E. Candelario-Jalil, D. Alvarez, A. González-Falcón, M. García-Cabrera, G. Martínez-Sánchez, N. Merino, A. Giuliani, O.S. León, Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia, Eur. J. Pharmacol. 453 (2002) 189-195. [10] E. Candelario-Jalil, D. Alvarez, J.M. Castañeda, S.M. Al-Dalain, G. Martínez, N. Merino, O.S. León, The highly selective cyclooxygenase-2 inhibitor DFU is neuroprotective when given several hours after transient cerebral ischemia in gerbils, Brain Res. 927 (2002) 212-215. [11] E. Candelario-Jalil, A. González-Falcón, M. García-Cabrera, D. Alvarez, S.M. Al-Dalain, G. Martínez, O.S. León, J.E. Springer, 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 (2003) 545–555. [12] E. Candelario-Jalil, D. Alvarez, N. Merino, O.S. León, Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils, Neurosci. Res. 47 (2003) 245-253. [13] P.E. Chabrier, M. Auguet, B. Spinnewyn, S. Auvin, S. Cornet, C. Demerlé-Pallardy, C. Guilmard-Favre, J.G. Marin, B. Pignol, V. Gillard-Roubert, C. Roussillot-Charnet, J. Schulz, I. Viossat, D. Bigg, S. Moncada, BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy, Proc. Natl. Acad. Sci. USA 96 (1999) 10824-10829. [14] J.A. Clemens, Cerebral ischemia: gene activation, neuronal injury, and the protective role of antioxidants, Free Radic. Biol. Med. 28 (2000) 1526-1531. [15] Y. Collaço-Moraes, B. Aspey, M. Harrison, J. de Belleroche, Cyclo-oxygenase-2 messenger RNA induction in focal cerebral ischemia, J. Cereb. Blood Flow Metab. 16 (1996) 1366-1372. [16] L. Cullen, L. Kelly, S.O. Connor, D.J. Fitzgerald, Selective cyclooxygenase-2 inhibition by nimesulide in man, J. Pharmacol. Exp. Ther. 287 (1998) 578-582. [17] P.K. Dash, S.A. Mach, A.N. Moore, Regional expression and role of cyclooxygenase-2 following experimental traumatic brain injury, J. Neurotrauma 17 (2000) 69-81. [18] G.J. del Zoppo, Clinical trials in acute stroke: why have they not been successful?, Neurology 51 (1998) S59-S61. [19] G. del Zoppo, I. Ginis, J.M. Hallenbeck, C. Iadecola, X. Wang, G.Z. Feuerstein, Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia, Brain Pathol. 10 (2000) 95-112. [20] W. Derk, M. Krieger, A. Abou-Chebl, J.C. Andrefsky, C.A. Sila, I. L. Katzan, M.R. Mayberg, A.J. Furlan, Cooling for Acute Ischemic Brain Damage (COOL AID): An Open Pilot Study of Induced Hypothermia in Acute Ischemic Stroke, Stroke 32 (2001) 1847-1854. [21] S. Dore, T. Otsuka, T. Mito, N. Sugo, T. Hand, L. Wu, P.D. Hurn, R.J. Traystman, K. Andreasson, Neuronal expression of cyclooxygenase-2 increases stroke damage, Ann. Neurol. 54 (2003) 155-162. [22] L.L. Dugan, D.W. Choi, Hypoxic-ischemic brain injury and oxidative stress. In: G.J. Siegel, B.W. Agranoff, R.W. Albers, S.K. Fisher, M.D. Uhler (Eds.), Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Lippincott-Raven Publishers, Philadelphia, 1999, pp. 711-729. [23] A.G. Dyker, K.R. Lees, Duration of neuroprotective treatment for ischemic stroke, Stroke 29 (1998) 535-542. [24] M. Fisher, J.H. Garcia, Evolving stroke and the ischemic penumbra, Neurology 47 (1996) 884-888. [25] A. González-Falcón, E. Candelario-Jalil, M. García-Cabrera, O.S. León, Effects of pyruvate administration on infarct volume and neurological deficits following permanent focal cerebral ischemia in rats, Brain Res. 990 (2003) 1-7. [26] S.H. Graham, J. Chen, Programmed cell death in cerebral ischemia, J. Cereb. Blood Flow Metab. 21 (2001) 99-109. [27] W. Hacke, M. Kaste, C. Fieschi, D. Toni, E. Lesaffre, R. von Kummer, G. Boysen, E. Bluhmki, G. Hoxter, M.H. Mahagne, Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS), JAMA 274 (1995) 1017-1025. [28] W. Hacke, T. Brott, L. Caplan, D. Meier, C. Fieschi, R. von Kummer, G. Donnan, W.D. Heiss, N.G. Wahlgren, M. Spranger, G. Boysen, J.R. Marler, Thrombolysis in acute ischemic stroke: controlled trials and clinical experience, Neurology 53 (1999) S3-S14. [29] S.J. Hewett, T.F. Uliasz, A.S. Vidwans, J.A. Hewett, Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture, J. Pharmacol. Exp. Ther. 293 (2000) 417-425. [30] S.L. Hickenbottom, J. Grotta, Neuroprotective therapy, Semin. Neurol. 18 (1998) 485-492. [31] D.L. Hirschberg, E. Yoles, M. Belkin, M. Schwartz, Inflammation after axonal injury has conflicting consequences for recovery of function: rescue of spared axons is impaired but regeneration is supported, J. Neuroimmunol. 50 (1994) 9-16. [32] A.J. Hunter, K.B. Mackay, D.C. Rogers, To what extent have functional studies of ischaemia in animals been useful in the assessment of potential neuroprotective agents?, Trends Pharmacol. Sci. 19 (1998) 59-66. [33] A.J. Hunter, J. Hatcher, D. Virley, P. Nelson, E. Irving, S.J. Hadingham, A.A. Parsons, Functional assessments in mice and rats after focal stroke, Neuropharmacology 39 (2000) 806–816. [34] C. Iadecola, M. Alexander, Cerebral ischemia and inflammation, Curr. Opin. Neurol. 14 (2001) 89-94. [35] C. Iadecola, C. Forster, S. Nogawa, H.B. Clark, M.E. Ross, Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia, Acta Neuropathol. 98 (1999) 9-14. [36] C. Iadecola, K. Niwa, S. Nogawa, X. Zhao, M. Nagayama, E. Araki, S. Morham, M. Ross, Reduced susceptibility to ischemic brain injury and NMDA-mediated neurotoxicity in cyclooxygenase-2-deficient mice, Proc. Natl. Acad. Sci. USA 98 (2001) 1294-1299. [37] K.A. Kelley, L. Ho, D. inger, J. Freire-Moar, C.B. Borelli, P.S. Aisen, G.M. Pasinetti, Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2, Am. J. Pathol. 155 (1999) 995-1004. [38] J. Koistinaho, S. Koponen, P.H. Chan, Expression of cyclooxygenase-2 mRNA after global ischemia is regulated by AMPA receptors and glucocorticoids, Stroke 30 (1999) 1900-1906. [39] J.M. Lee, G.J. Zipfel, K.H. Park, Y.Y. He, C.Y. Hsu, D.W. Choi, Zinc translocation accelerates infarction after mild transient focal ischemia, Neuroscience 115 (2002) 871-878. [40] Q. Li, D. Stephenson, Postischemic administration of basic fibroblast growth factor improves sensorimotor function and reduces infarct size following permanent focal cerebral ischemia in the rat, Exp. Neurol. 177 (2002) 531-537. [41] E.Z. Longa, P.R. Weinstein, S. Carlson, R. Cummins, Reversible middle cerebral artery occlusion without craniectomy in rats, Stroke 20 (1989) 84-91. [42] L. Marnett, S. Rowlinson, D. Goodwin, A. Kalgutkar, C. Lanzo, Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition, J. Biol. Chem. 274 (1999) 22903-22906. [43] S. Miettinen, F.R. Fusco, J. Yrjanheikki, R. Keinanen, T. Hirvonen, R. Roivainen, M. Narhi, T. Hokfelt, J. Koistinaho, 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 (1997) 6500-6505. [44] K. Minematsu, L. Li, C.H. Sotak, M.A. Davis, M. Fisher, Reversible focal ischemic injury demonstrated by diffusion-weighted magnetic resonance imaging in rats, Stroke 23 (1992) 1304-1310. [45] M. Mirjany, L. Ho, G.M. Pasinetti, Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity, J. Pharmacol. Exp. Ther. 301 (2002) 494-500. [46] M. Modo, P. Rezaie, P. Heuschling, S. Patel, D.K. Male, H. Hodges, Transplantation of neural stem cells in a rat model of stroke: assessment of short-term graft survival and acute host immunological response, Brain Res. 958 (2002) 70-82. [47] N. J. Mulcahy, J. Ross, N.J. Rothwell, S.A. Loddick, Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat, Br. J. Pharmacol. 140 (2003) 471–476. [48] N. Nagai, M. de Mol, B. van Hoef, M. Verstreken, M. Collen, Depletion of circulating alpha(2)-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization, Blood 97 (2001) 3086-3092. [49] M. Nagayama, K. Niwa, T. Nagayama, M.E. Ross, C. Iadecola, 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 (1999) 1213-1219. [50] M. Nakayama, K. Uchimura, R.L. Zhu, T. Nagayama, M.E. Rose, R.A. Stetler, P.C. Isakson, J. Chen, S.H. Graham, Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia, Proc. Natl. Acad. Sci. USA 95 (1998) 10954-10959. [51] S. Nogawa, F. Zhang, M.E. Ross, C. Iadecola, Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage, J. Neurosci. 17 (1997) 2746-2755. [52] S. Nogawa, C. Forster, F. Zhang, M. Nagayama, M.E. Ross, C. Iadecola, Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia, Proc. Natl. Acad. Sci. USA 95 (1998) 10966-10971. [53] B. Onténiente, C. Couriaud, J. Braudeau, A. Benchoua, C. Guégan, The mechanisms of cell death in focal cerebral ischemia highlight neuroprotective perspectives by anti-caspase therapy, Biochem. Pharmacol. 66 (2003) 1643–1649. [54] S. Parmentier, G.A. Bohme, D. Lerouet, D. Damour, J.M. Stutzmann, I. Margaill, M. Plotkine, Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury, Br. J. Pharmacol. 127 (1999) 546-552. [55] A.M. Planas, M.A. Soriano, E. Rodríguez-Farré, I. Ferrer, Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain, Neurosci. Lett. 200 (1995) 187-190. [56] A.M. Planas, M.A. Soriano, C. Justicia, E. Rodríguez-Farré, 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 (1999) 141-144. [57] W.S. Powell, Rapid extraction of arachidonic acid metabolites from biological samples using octadecylsilyl silica. In: Lands, W.E.M., Smith, W.L., (Eds), Methods in Enzymology. Academic Press, Orlando, 1982, pp. 466-477. [58] V.L.R. Rao, A. Dogan, K.G. Todd, K.K. Bowen, B.T. Kim, J.D. Rothstein, R.J. Dempsey, Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain, J. Neurosci. 21 (2001) 1876-1883. [59] D. Reglodi, A. Somogyvari-Vigh, S. Vigh, T. Kozicz, A. Arimura, Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat, Stroke 31 (2000) 1411-1417. [60] T. Sairanen, A. Ristimaki, A. Paetau, P.J. Lindsberg, Cyclooxygenase-2 is induced globally in infarcted human brain, Ann. Neurol. 43 (1998) 738-747. [61] O. Sanz, A. Estrada, I. Ferrer, A.M. Planas, Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid, Neuroscience 80 (1997) 221-232. [62] T. Sasaki, K. Kitagawa, K. Yamagata, T. Takemiya, S. Tanaka, E. Omura-Matsuoka, S. Sugiura, M. Matsumoto, M. Hori, Amelioration of hippocampal neuronal damage after transient forebrain ischemia in cyclooxygenase-2-deficient mice, J. Cereb. Blood Flow Metab. 24 (2004) 107–113. [63] S.I. Savitz, D.M. Rosenbaum, J.H. Dinsmore, L.R. Wechsler, L.R. Caplan LR, Cell transplantation for stroke, Ann. Neurol. 52 (2002) 266-275. [64] R. Schmid-Elsaesser, E. Hungerhuber, S. Zausinger, A. Baethmann, H. J. Reulen, Neuroprotective efficacy of combination therapy with two different antioxidants in rats subjected to transient focal ischemia, Brain Res. 816 (1999) 471-479. [65] S. Schwab, S. Schwarz, M. Spranger, E. Keller, M. Bertram, W. Hacke, Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction, Stroke 29 (1998) 2461-2466. [66] A. Shuaib, C.X. Wang, T. Yang, R. Noor, Effects of nonpeptide V(1) vasopressin receptor antagonist SR-49059 on infarction volume and recovery of function in a focal embolic stroke model, Stroke 33 (2002) 3033-3037. [67] A.L. Sirén, M. Fratelli, M. Brines, C. Goemans, S. Casagrande, P. Lewczuk, S. Keenan, C. Gleiter, C. Pasquali, A. Capobianco, T. Mennini, R. Heulmann, A. Cerami, H. Ehrenreich, P. Ghezzi, Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress, Proc. Natl. Acad. Sci. USA 98 (2001) 4044-4049. [68] Stroke Therapy Academy Industry Roundtable (STAIR II), Recommendation for clinical trial evaluation of acute stroke therapies, Stroke 32 (2001) 1598-1606. [69] Y. Taniguchi, K. Yokoyama, K. Noda, Inhibition of brain cyclooxygenase-2 activity and the antipyretic action of nimesulide, Eur. J. Pharmacol. 330 (1997) 221-229. [70] The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, Tissue plasminogen activator for acute ischemic stroke, New England J. Med. 333 (1995) 1581-1587. [71] P.L. Toutain, C.C. Cester, T. Haak, S. Metge, Pharmacokinetic profile and in vitro selective cyclooxygenase-2 inhibition by nimesulide in the dog, J. Vet. Pharmacol. Ther. 24 (2001) 35-42. [72] M. van Lookeren Campagne, H. Thibodeaux, N. Bruggen, B. Cairns, R. Gerlai, J.T. Palmer, S.P. Williams, D.G. Lowe, Evidence for a protective role of metallothionein-1 in focal cerebral ischemia, Proc. Natl. Acad. Sci. USA, 96 (1999) 12870–12875. [73] J. Vaughan, N. Delanty, Neuroprotective properties of statins in cerebral ischemia and stroke, Stroke 30 (1999) 1969-1973. [74] J. Wang, X. Yang, C.V. Camporesi, Z. Yang, G. Bosco, C. Chen, E.M. Camporesi, Propofol reduces infarct size and striatal dopamine accumulation following transient middle cerebral artery occlusion: a microdialysis study, Eur. J. Pharmacol. 452 (2002) 303-308. [75] J.H. Weiss, S.L. Sensi, J.Y. Koh, Zn2+: a novel ionic mediator of neural injury in brain disease, Trends Pharmacol. Sci. 21 (2000) 395-401. [76] A.J. Williams, F.C. Tortella, Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat, Brain Res. 932 (2002) 45-55. [77] K. Yamagata, K.I. Andreasson, P.F. Worley, Expression of a mitogen-inducible cyclooxygenase in brain neurons, regulation by synaptic activity and glucocorticoids, Neuron 11 (1993) 371-386. [78] Y. Yang, A. Shuaib, Q. Li, Quantification of infarct size on focal cerebral ischemia model of rats using a simple and economical method, J. Neurosci. Meth. 84 (1998) 9-16. [79] Y. Yang, Q. Li, H. Miyashita, W. Howlett, M. Siddiqui, A. Shuaib, Usefulness of postischemic thrombolysis with or without neuroprotection in a focal embolic model of cerebral ischemia, J. Neurosurg. 92 (2000) 841-847. [80] M.A. Yenari, S.L. Fink, G.H. Sun, L.K. Chang, M.K. Patel, D.M. Kunis, D. Onley, D.Y. Ho, R.M. Sapolsky, G.K. Steinberg, Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy, Ann. Neurol. 44 (1998) 584-591. [81] M.A. Yenari, H. Zhao, R.G. Giffard, R.A. Sobel, R.M. Sapolsky, G.K. Steinberg, Gene therapy and hypothermia for stroke treatment, Ann. NY Acad. Sci. 993 (2003) 54-81. relation_type: [] relation_uri: [] reportno: ~ rev_number: 12 series: ~ source: ~ status_changed: 2007-09-12 17:11:00 subjects: - neuro-chem succeeds: ~ suggestions: ~ sword_depositor: ~ sword_slug: ~ thesistype: ~ title: Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat type: journalp userid: 6903 volume: 1007