Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643.
This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 on ischemia/reperfusion (I/R) injury in the rat hippocampus. Transient cerebral ischemia (30 min), followed by 1-24 h reperfusion, significantly increased the generation of reactive oxygen species, nitric oxide (NO), and lipid peroxidation end-products, as well as markedly reducing levels of the endogenous antioxidant glutathione. Reperfusion for 3-6 h led to increased expression of the proteins heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). Pretreatment with WY14643 suppressed oxidative stress and expression of HO-1, iNOS, and ICAM-1, but had no effect on COX-2. These effects are due to suppression of the activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB. The PPAR-alpha antagonist MK886 abolished the beneficial effects of WY14643. The levels of S100B protein, a marker of cerebral injury used in stroke trials to monitor injury, were high in the hippocampus of rats exposed to I/R, but markedly reduced by WY14643. We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke.
Collino
Massimo
M
Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, 10125 Turin, Italy. massimo.collino@unito.it
Aragno
Manuela
M
Mastrocola
Raffaella
R
Benetti
Elisa
E
Gallicchio
Margherita
M
Dianzani
Chiara
C
Danni
Oliviero
O
Thiemermann
Christoph
C
Fantozzi
Roberto
R
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015227:Lipid Peroxidation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*
D016328:NF-kappa B; D047493:PPAR alpha; D011743:Pyrimidines; D018799:Intercellular Adhesion Molecule-1; C006253:pirinixic acid; D052247:Nitric Oxide Synthase Type II; D006419:Heme Oxygenase (Decyclizing); D051546:Cyclooxygenase 2