Altered PPARgamma 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-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.
Victor
N A
NA
Department of Neurology, Case Western Reserve University, 11100 Euclid Ave., Cleveland, Ohio 44106, USA.
Wanderi
E W
EW
Gamboa
J
J
Zhao
X
X
Aronowski
J
J
Deininger
K
K
Lust
W D
WD
Landreth
G E
GE
Sundararajan
S
S
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use; D013997:Time Factors
D001549:Benzamides; D047495:PPAR gamma; D011725:Pyridines; D012333:RNA, Messenger; C458508:T 0070907; D045162:Thiazolidinediones; D000077154:Rosiglitazone