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.

中文翻译：

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褪黑素降低大鼠短暂性局灶性脑缺血后基质金属蛋白酶9的激活和表达，并减轻再灌注引起的出血。

先前我们已经表明，褪黑素可降低缺血性卒中后缺血后血脑屏障（BBB）通透性的升高，并改善神经血管功能障碍和出血性转化。已知基质金属蛋白酶（MMP）的激活在缺血性中风后脑水肿和出血性转化的发病机理中起着至关重要的作用。在本文中，我们研究了褪黑激素是否会改善短暂性局灶性脑缺血大鼠模型中的MMP-2和MMP-9活化和表达。使用腔内灯丝对成年雄性Sprague-Dawley大鼠进行90分钟的大脑中动脉（MCA）阻塞。再灌注后静脉注射褪黑激素（5 mg / kg）或赋形剂。测量了脑梗塞和梗塞内的出血，并对神经功能缺损进行了评分。通过酶谱，原位酶谱和Western免疫印迹分析确定MMP-2和MMP-9的活性和表达。脑缺血再灌注诱导的再灌注发作后24小时增加了pro-MMP-9和MMP-9的活性和表达。相对于对照，褪黑素治疗的动物除减少脑梗死体积和出血性转化以及改善感觉运动神经行为结果外，其MMP-9活性和表达水平显着降低（P <0.01）。在整个实验过程中，未观察到MMP-2活性的显着变化。我们的结果表明，褪黑素介导的缺血性脑损伤减少和再灌注引起的出血减少部分归因于其减少缺血后MMP-9激活和表达增加的能力，