Altered PPARgamma expression and activation after transient focal ischemia in rats.

Victor NA, Wanderi EW, Gamboa J, Zhao X, Aronowski J, Deininger K, Lust WD, Landreth GE, Sundararajan S
Eur J Neurosci. 2006 24 (6): 1653-63

PMID: 17004929 · DOI:10.1111/j.1460-9568.2006.05037.x

Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists troglitazone and pioglitazone reduce injury and inflammation in a rat model of transient cerebral ischemia. The mechanism of this protection is unclear, as these agents can act through PPAR-gamma activation or through PPAR-gamma-independent mechanisms. Therefore, we examined PPAR-gamma expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR-gamma antagonist, T0070907, to determine the role of PPAR-gamma during ischemia. Using immunohistochemical techniques and real-time PCR, we found low levels of PPAR-gamma mRNA and PPAR-gamma immunoreactivity in nonischemic brain; however, PPAR-gamma expression dramatically increased in ischemic neurons, peaking 24 h following middle cerebral artery occlusion. Interestingly, we found that in both vehicle- and agonist-treated brains, DNA binding was reduced in the ischemic hemisphere relative to the contralateral hemisphere. Expression of a PPAR-gamma target gene, lipoprotein lipase, was also reduced in ischemic relative to nonischemic brain. Both DNA binding and lipoprotein lipase expression were increased by the addition of the PPAR-gamma agonist rosiglitazone. Finally, we found that rosiglitazone-mediated protection after stroke was reversed by the PPAR-gamma antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR-gamma agonist, suggesting that endogenous PPAR-gamma ligands may mitigate the effects of cerebral ischemia.

MeSH Terms (17)

Animals Benzamides Enzyme Activation Gene Expression Regulation Immunohistochemistry Ischemic Attack, Transient Male PPAR gamma Protein Binding Pyridines Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Rosiglitazone Thiazolidinediones Time Factors

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