Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury.
BACKGROUND
Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance.


METHODS
The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed.


RESULTS
UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect.


CONCLUSIONS
UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.
Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
Yanzhe
Y
Wang
Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
Zhiyi
Z
He
Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
Shumin
S
Deng
D000284:Administration, Oral; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000097245:Ursolic Acid; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D045726:Metalloproteases; D018696:Neuroprotective Agents; D014315:Triterpenes; D000097245:Ursolic Acid; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds
brain ischemia; matrix metalloproteases; peroxisome proliferator-activated receptors; ursolic acid