Zhao Bing-Qiao, Wang Sophia, Kim Hahn-Young, Storrie Hannah, Rosen Bruce R, Mooney David J, Wang Xiaoying, Lo Eng H
Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149-2401, Charlestown, Massachusetts 02129, USA.
Nat Med. 2006 Apr;12(4):441-5. doi: 10.1038/nm1387. Epub 2006 Mar 26.
Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. 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. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. 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.
基质金属蛋白酶（MMPs）是一类锌内肽酶，在中枢神经系统（CNS）的生理和病理过程中具有多方面的作用。越来越多的数据表明，MMPs在中风中起有害作用。通过降解神经血管基质，MMPs促进血脑屏障损伤、水肿和出血。通过破坏细胞-基质信号传导和内环境稳态，MMPs引发脑细胞死亡。因此，人们正在朝着开发用于急性中风治疗的MMP抑制剂的方向努力。但MMPs在中风后的延迟阶段可能具有不同的作用。由于MMPs调节脑基质，它们可能在中风恢复过程中介导有益的可塑性和重塑。在此，我们表明MMPs参与大鼠局灶性脑缺血后的延迟皮质反应。MMP-9在中风后7-14天在梗死周围皮质中上调，并与神经血管重塑标志物共定位。中风后7天用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MMPs会降低内源性VEGF信号，而额外用外源性VEGF治疗可防止MMP抑制剂引起的梗死恶化。这些数据表明，与急性中风的MMP抑制剂疗法相反，促进中风恢复可能需要调节MMPs的策略。
