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.