The role of nitric oxide in the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats.
Cortical spreading depression (CSD) has been documented to confer ischemic tolerance on brain. Although nitric oxide (NO) is a crucial mediator in preconditioning under certain circumstances, the role of NO in CSD-induced neuroprotection is unclear. We examined the effect of L-NAME, an inhibitor of NO synthase, on CSD-induced tolerance against transient focal cerebral ischemia. A solution of 0.5 M KCl was applied for 2 h on the right hemisphere to induce CSD. Animals received either vehicle or L-NAME (4 mg/kg, iv) 30 min before CSD. Temporary occlusion (120 min) of the right middle cerebral artery was induced 4 days after preconditioning and the infarct volume was measured. Additionally, ERK 1/2 activation and cyclooxygenase-2 (COX-2) expression in the cerebral cortex were examined by Western blotting analysis immediately after cessation of CSD, or at 1, 2, 4, 8, and 24 h after CSD. CSD reduced infarct volume from 275 +/- 15 mm3 (mean +/- SEM) in the non-CSD group to 155 +/- 14 mm3 in the CSD group (P < 0.05). L-NAME abolished this protection (281 +/- 14 mm3; P < 0.05 vs. CSD group). Elevated ERK activation and COX-2 expression were observed immediately after or 8 h after preconditioning, respectively. Those responses are significantly augmented by L-NAME (3-fold for ERK and 4-fold for COX-2). These results suggest a crucial role of NO in the establishment of preconditioning with CSD.
Horiguchi
Takashi
T
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA.
Snipes
James A
JA
Kis
Bela
B
Shimizu
Katsuyoshi
K
Busija
David W
DW
D000818:Animals; D001921:Brain / Q000098:blood supply; D013181:Cortical Spreading Depression / Q000502:physiology*; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D019194:Ischemic Preconditioning; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009410:Nerve Degeneration / Q000201:enzymology / Q000517:prevention & control; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048049:Extracellular Signal-Regulated MAP Kinases; D019331:NG-Nitroarginine Methyl Ester