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

• Published in: The FASEB journal Vol. 20; no. 8; p. 1162
• Main Authors: Zhao, Yi, Patzer, Andreas, Herdegen, Thomas, Gohlke, Peter, Culman, Juraj
• Format: Journal Article
• Language: English
• Published: United States 01.06.2006
• Subjects: Animals; Brain Ischemia - enzymology; Brain Ischemia - metabolism; Cell Survival; Cerebral Cortex - chemistry; Cerebral Cortex - cytology; Cerebral Cortex - enzymology; Cerebrovascular Circulation - drug effects; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - analysis; Cyclooxygenase 2 - metabolism; Male; Neurons - enzymology; Neurons - metabolism; Neuroprotective Agents - pharmacology; Oxidative Stress; PPAR gamma - agonists; PPAR gamma - analysis; PPAR gamma - metabolism; Rats; Rats, Wistar; Thiazolidinediones - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1530-6860
• DOI: 10.1096/fj.05-5007com

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.