Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats.
Up-regulation of cyclooxygenase (COX)-2 exacerbates neuronal injury after cerebral ischemia and contributes to neuronal cell death. The present study clarifies the function of cerebral peroxisome-proliferator-activated receptor(s) gamma (PPARgamma) in the expression of COX-2 in neurons of the rat brain after middle cerebral artery occlusion (MCAO) with reperfusion by immunohistochemistry, Western blot, and immunofluorescence staining. In peri-infarct cortical areas the PPARgamma was located in both microglia and neurons, whereas COX-2 was almost exclusively expressed in neurons. PPARgamma immunolabeling reached the peak 12 h after MCAO, whereas the number of COX-2 immunostained cells gradually rose and reached its peak at 48 h. Intracerebroventricular infusion of pioglitazone, an agonist of the PPARgamma, over a 5-day period before and 2 days after MCAO, reduced the infarct size, the expression of tumor necrosis factor alpha (TNF-alpha), COX-2, and the number of cells positively stained for COX-1 and COX-2 in the peri-infarct cortical regions. COX-2 induction was also attenuated in the ipsilateral but not in the contralateral hippocampus. In primary cortical neurons expressing the PPARgamma, pioglitazone suppressed COX-2 expression in response to oxidative stress. This protective effect was reversed after cotreatment with GW 9662, a selective antagonist of the PPARgamma, clearly demonstrating a PPARgamma-dependent mechanism. Our data provide evidence that activation of neuronal PPARgamma considerably contributes to neuroprotection by prevention of COX-2 up-regulation in vitro and in peri-infarct brain areas.
Zhao
Yi
Y
Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel Hospitalstrasse 4 24105 Kiel, Germany.
Patzer
Andreas
A
Herdegen
Thomas
T
Gohlke
Peter
P
Culman
Juraj
J
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D002470:Cell Survival; D002540:Cerebral Cortex / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000077205:Pioglitazone