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.

Protective Effect of Melatonin upon Neuropathology, Striatal Function, and Memory Ability after Intracerebral Hemorrhage in Rats

“…In fact, MMP-9-null mice experienced greater hemorrhagic volume, brain edema, and diminished neurological function than wild-type controls . The downregulation of MMP-9 by melatonin (Hung et al, 2008) may account for the differences between our equivocal short-term findings (i.e., brain edema and neurological function) and the benefits reported after free-radical reduction with edaravone in an autologous blood injection model (Nakamura et al, 2008).…”

“…Melatonin (5 mg=kg) has been shown to reduce blood-brain barrier permeability and the hemorrhagic transformation into ICH after ischemic stroke in mice (Chen et al, 2006b), and this reduction in bleeding is likely to be mediated by attenuation of matrix metalloproteinase (MMP)-9 activation (Hung et al, 2008). Similar findings relating to MMP-9 and hemorrhagic transformation have been reported after edaravone treatment in rats (Yagi et al, 2009).…”

Melatonin modulates the effects of diethylstilbestrol (DES) on the anterior pituitary of the female Wistar rat.

“…The present study demonstrated DESinduced upregulation of VEGF and MMP-9, confirming a role for estrogen in angiogenesis in the rat anterior pituitary. Melatonin has been reported to downregulate MMP-9 expression and activity in several pathological states in rodents, such as reperfusioninduced hemorrhage following transient focal cerebral ischemia and spinal cord injury [29][30][31]. The inhibitory effects of melatonin may be associated with reduced expression of TNF-α and elevated expression of tissue inhibitor of metalloproteinase (TIMP)-1 [30,32].…”

Astaxanthin reduces matrix metalloproteinase-9 expression and activity in the brain after experimental subarachnoid hemorrhage in rats

“…The activity of MMP-9 was measured as previously described (Hung et al, 2008). Briefly, brain samples were homogenized and centrifuged.…”