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Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

Authors Wang Y, He Z, Deng S

Received 7 January 2016

Accepted for publication 14 March 2016

Published 17 May 2016 Volume 2016:10 Pages 1663—1674

DOI https://doi.org/10.2147/DDDT.S103829

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lucy Goodman

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Wei Duan


Yanzhe Wang, Zhiyi He, Shumin Deng

Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China

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.
Conclusion:
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.

Keywords:
brain ischemia, ursolic acid, peroxisome proliferator-activated receptors, matrix metalloproteases

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