title: Melatonin decreases matrix metalloproteinase-9 activation and expression and attenuates reperfusion-induced hemorrhage following transient focal cerebral ischemia in rats.
abstract: We have previously shown that melatonin reduces postischemic rises in the blood-brain barrier (BBB) permeability and improves neurovascular dysfunction and hemorrhagic transformation following ischemic stroke. It is known that activation of the matrix metalloproteinases (MMPs) plays a crucial role in the pathogenesis of brain edema and hemorrhagic transformation after ischemic stroke. We, herein, investigated whether melatonin would ameliorate MMP-2 and MMP-9 activation and expression in a rat model of transient focal cerebral ischemia. Adult male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery (MCA) occlusion using an intraluminal filament. Melatonin (5 mg/kg) or vehicle was intravenously injected upon reperfusion. Brain infarction and hemorrhage within infarcts were measured, and neurological deficits were scored. The activity and expression of MMP-2 and MMP-9 were determined by zymography, in situ zymography and Western immunoblot analysis. Cerebral ischemia-reperfusion induced increased pro-MMP-9 and MMP-9 activity and expression 24 hr after reperfusion onset. Relative to controls, melatonin-treated animals, however, had significantly reduced levels in the MMP-9 activity and expression (P < 0.01), in addition to reduced brain infarct volume and hemorrhagic transformation as well as improved sensorimotor neurobehavioral outcomes. No significant change in MMP-2 activity was observed throughout the course experiments. Our results indicate that the melatonin-mediated reductions in ischemic brain damage and reperfusion-induced hemorrhage are partly attributed to its ability to reduce postischemic MMP-9 activation and increased expression, and further support the fact that melatonin is a suitable as an add-on to thrombolytic therapy for ischemic stroke patients.
authors.affiliation: Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan.
authors.forename: Yu-Chang
authors.initials: YC
authors.lastname: Hung
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Chen
authors.forename: E-Jian
authors.initials: EJ
authors.lastname: Lee
authors.forename: Wan-Ling
authors.initials: WL
authors.lastname: Chen
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Huang
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Lee
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Lee
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018709:Statistics, Nonparametric
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008550:Melatonin