Role of matrix metalloproteinases in delayed cortical responses after stroke
Role of matrix metalloproteinases in delayed cortical responses after stroke
复制标题
DOI：
10.1038/nm1387
复制
发表时间：
2006-04-01
期刊：
影响因子：
82.9
通讯作者：
Lo, EH
中科院分区：
文献类型：
--
作者：
Zhao, BQ;Wang, S;Lo, EH
基质金属蛋白酶 (MMP) 是一种锌内肽酶，在中枢神经系统 (CNS) 生理学和病理学中具有多因素作用 (1)。越来越多的数据表明 MMP 对中风具有有害作用。 MMP 通过降解神经血管基质，促进血脑屏障损伤、水肿和出血(2-4)。通过破坏细胞基质信号传导和稳态，MMP 会引发脑细胞死亡(5,6)。因此，出现了开发用于急性中风治疗的 MMP 抑制剂的趋势。但 MMP 在中风后的延迟期可能发挥不同的作用。由于 MMP 调节脑基质，因此它们可能在中风恢复期间介导有益的可塑性和重塑。在这里，我们证明 MMP 参与大鼠局灶性脑缺血后延迟的皮质反应。中风后 7-14 天，MMP-9 在梗死周围皮层中表达上调，并与神经血管重塑标记物共定位。中风后 7 天使用 MMP 抑制剂治疗可抑制神经血管重塑，增加缺血性脑损伤，并在 14 天时损害功能恢复。生物可利用的 VEGF 的 MMP 加工可能参与其中，因为抑制 MMP 会减少内源性 VEGF 信号，而用外源性 VEGF 进行额外治疗可防止 MMP 抑制剂诱导的梗塞恶化。这些数据表明，与急性中风的 MMP 抑制剂疗法相反，可能需要调节 MMP 的策略来促进中风恢复。
Matrix metalloproteinases ( MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology(1). Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage(2-4). By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death(5,6). Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.