Altered PPARγ expression and activation after transient focal ischemia in rats

Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator‐activated receptor‐γ (PPARγ) 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‐γ activation or through PPAR‐γ‐independent mechanisms. Therefore, we examined PPAR‐γ expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR‐γ antagonist, T0070907, to determine the role of PPAR‐γ during ischemia. Using immunohistochemical techniques and real‐time PCR, we found low levels of PPAR‐γ mRNA and PPAR‐γ immunoreactivity in nonischemic brain; however, PPAR‐γ 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‐γ 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‐γ agonist rosiglitazone. Finally, we found that rosiglitazone‐mediated protection after stroke was reversed by the PPAR‐γ antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR‐γ agonist, suggesting that endogenous PPAR‐γ ligands may mitigate the effects of cerebral ischemia.