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Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats

Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany

¹Correspondence: Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel Hospitalstrasse 4 24105 Kiel, Germany. E-mail: juraj.culman{at}pharmakologie.uni-kiel.de

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 (PPAR) 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 PPAR was located in both microglia and neurons, whereas COX-2 was almost exclusively expressed in neurons. PPAR 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 PPAR, over a 5-day period before and 2 days after MCAO, reduced the infarct size, the expression of tumor necrosis factor (TNF-), 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 PPAR, 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 PPAR, clearly demonstrating a PPAR-dependent mechanism. Our data provide evidence that activation of neuronal PPAR considerably contributes to neuroprotection by prevention of COX-2 up-regulation in vitro and in peri-infarct brain areas.—Zhao, Y., Patzer, A., Herdegen, T., Gohlke, P., Culma, J. Activation of cerebral peroxisome proliferator-activated receptors gamma (PPAR) promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats.

Key Words: cerebral ischemia • PPAR • pioglitazone • cyclooxygenase-2 • cyclooxygenase-1 • rat

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