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