Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia

Shih-Huang Tai, Hung Yi Chen, E-Jian Lee, Tsung Ying Chen, Hsiao Wen Lin, Yu-Chang Hong, Sheng Yang Huang, Ying Hsin Chen, Wei Ting Lee, Tian-Shung Wu

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

We have shown that melatonin attenuated matrix metalloproteinase-9 (MMP-9) activation and decreased the risk of hemorrhagic transformation following cerebral ischemia-reperfusion. Herein, we investigate the possible involvement of the plasminogen/plasmin system and endogenous MMPs inhibitor underlying the melatonin-mediated MMP-9 inhibition. Mice were subjected to 1-hr ischemia and 48-hr reperfusion of the right middle cerebral artery. Melatonin (5 mg/kg) or vehicle was intravenously injected upon reperfusion. Brain infarction and hemorrhagic transformation were measured. Extracellular matrix damage was determined by Western immunoblot analysis for laminin protein. The activity and expression of MMP-2 and MMP-9 were determined by gelatin zymography, in situ zymography, and Western immunoblot analysis. In addition, the activities of tissue and urokinase plasminogen activators (tPA and uPA) were evaluated by plasminogen-dependent casein zymography. Endogenous plasminogen activator inhibitor (PAI) and tissue inhibitors of MMP (TIMP-1) were investigated using enzyme-linked immunosorbent assay (ELISA) and Western immunoblot analysis, respectively. Cerebral ischemia-reperfusion induced increased MMP-9 activity and expression at 12-48 hr after reperfusion onset. Relative to controls, melatonin-treated animals had significantly decreased MMP-9 activity and expression (P < 0.05), in addition to reduced brain infarction and hemorrhagic transformation as well as improved laminin protein preservation. This melatonin-mediated MMP-9 inhibition was accompanied by reduced uPA activity (P < 0.05), as well as increased TIMP-1 expression and PAI activity (P < 0.05, respectively). These results demonstrate the melatonins pluripotent mechanisms for attenuating postischemic MMP-9 activation and neurovascular damage, and further support it as an add-on to thrombolytic therapy for ischemic stroke patients.

Original languageEnglish
Pages (from-to)332-341
Number of pages10
JournalJournal of Pineal Research
Volume49
Issue number4
DOIs
Publication statusPublished - 2010 Nov 1

All Science Journal Classification (ASJC) codes

  • Endocrinology

Fingerprint Dive into the research topics of 'Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia'. Together they form a unique fingerprint.

  • Cite this