Cyclooxygenase-2 mediates the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats.
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-Delta(12, 14) PGJ2 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 mm3) when cortical spreading depression was performed 3 and 4 days before middle cerebral artery occlusion (163.9+/-14.2 mm3, 154.9+/-14.2 mm3) but not at 1, 2 and 5 days (280.4+/-17.3 mm3, 276.3+/-16.9 mm3 and 268.5+/-17.3 mm3). 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-Delta(12, 14) PGJ2 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 mm3). 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 mm3). 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.
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, USA, and Department of Neurosurgery, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo, Japan. takaholy@aol.com
T
T
Horiguchi
J A
JA
Snipes
B
B
Kis
K
K
Shimizu
D W
DW
Busija
D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology* / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D013181:Cortical Spreading Depression / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000201:enzymology* / Q000503:physiopathology; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D052246:Cyclooxygenase 2 Inhibitors; D009569:Nitric Oxide; C037112:9-deoxy-delta-9-prostaglandin D2; D011189:Potassium Chloride; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2; D019331:NG-Nitroarginine Methyl Ester