Cyclooxygenase-2 mediates the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats

T. Horiguchi, J. A. Snipes, B. Kis, K. Shimizu, D. W. Busija

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21 Citations (Scopus)


We examined the role of cyclooxygenase-2 in the development of ischemic tolerance induced by cortical spreading depression against transient, focal brain ischemia. Cortical spreading depression was continuously induced for 2 h with topical KCl (13±1 depolarizations/2 h) in male Wistar rats. At 1, 2, 3, 4, and 5 days following recovery, the middle cerebral artery was transiently occluded for 120 min. Four days later, the animals were killed and infarct volume was determined. Additionally, cyclooxygenase-2 levels in the cerebral cortex and 15 deoxy-Δ(12, 14) PGJ 2 levels in cerebrospinal fluid were determined at these times with Western blotting and immunoassay, respectively. Infarct volume was reduced compared with non-cortical spreading depression control animals (274.3±15.3 mm 3) when cortical spreading depression was performed 3 and 4 days before middle cerebral artery occlusion (163.9±14.2 mm 3, 154.9±14.2 mm 3) but not at 1, 2 and 5 days (280.4±17.3 mm 3, 276.3±16.9 mm 3 and 268.5±17.3 mm 3). Cyclooxygenase-2 levels increased most dramatically starting at 2 days, peaked at 3 days, and started to return toward baseline at 4 days after cortical spreading depression. 15 Deoxy-Δ(12, 14) PGJ 2 levels increased from 134.7±83 pg/ml at baseline to 718±98 pg/ml at 3 days. Administration of N-[2-cyclohexyloxy-4-nitrophenyl] methanesulphonamide (10 mg/kg, i.v.), a selective cyclooxygenase-2 inhibitor, at 1 h prior to middle cerebral artery occlusion in cortical spreading depression preconditioned animals did not affect infarct volume (162.6±62.1 mm 3). However, administration of N-[2-cyclohexyloxy-4-nitrophenyl] methanesulphonamide given three times prior to middle cerebral artery occlusion prevented the reduced infarct volume induced by cortical spreading depression preconditioning (272.9±63.2 mm 3). Administration of l-nitro-arginine methyl ester (4 mg/kg, i.v.) prior to cortical spreading depression blocked increases in cyclooxygenase-2 normally seen at 3 and 4 days. We conclude that NO-mediated cyclooxygenase-2 upregulation by cortical spreading depression protects the brain against ischemic damage.

Original languageEnglish
Pages (from-to)723-730
Number of pages8
Issue number2
Publication statusPublished - 2006
Externally publishedYes


  • cerebral blood flow
  • neuroprotection
  • nitric oxide
  • nitric oxide synthase
  • stroke

ASJC Scopus subject areas

  • Neuroscience(all)


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