Rosiglitazone alone or in combination with tissue plasminogen activator improves ischemic brain injury in an embolic model in rats.
In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, is neuroprotective in focal ischemic brain injury, and whether rosiglitazone can enhance the protective action of tissue plasminogen activator (tPA), an agent used clinically for thrombolytic therapy. Rats were subjected to ischemic brain injury by embolizing preformed clots into the middle cerebral artery (MCA). Treatment with rosiglitazone reduced infarction and improved functional recovery; it also enhanced the neuroprotective action of tPA and lengthened the time window for initiating tPA treatment. Occlusion of MCA resulted in a loss of collagen type IV, a major structural protein of the microvascular basal lamina, and tPA treatment worsened this loss. Rosiglitazone treatment prevented the reduction of collagen type IV in the ischemic injured brain by inhibiting the activation of matrix metallopeptidase-9 (MMP-9). In addition, rosiglitazone treatment reduced inflammatory reactions in the ischemic injured brain. Rosiglitazone either alone or in combination with tPA is an effective agent in the reduction of ischemic brain injury. The reduction of microvascular damage and inflammation contributes to the beneficial actions of rosiglitazone.
Wang
Chen Xu
CX
Stroke Research Laboratory, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. cwang3@ilstu.edu
Ding
Xiuqing
X
Noor
Raza
R
Pegg
Christina
C
He
Chunyan
C
Shuaib
Ashfaq
A
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D024141:Collagen Type IV / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004617:Embolism / Q000150:complications; D007004:Hypoglycemic Agents; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D020768:Middle Cerebral Artery; D018696:Neuroprotective Agents; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
D024141:Collagen Type IV; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9