Evidence of the pathological roles of
matrix metalloproteinases (
MMPs) in various
neurological disorders has made them attractive therapeutic targets.
MMPs disrupt the blood-brain barrier and cause neuronal death and
neuroinflammation in acute
cerebral ischemia and are critical for angiogenesis during recovery. However, some challenges have to be overcome before
MMPs can be further validated as drug targets in
stroke injury. Identifying in vivo substrates of
MMPs should greatly improve our understanding of the mechanisms of ischemic injury and is critical for providing more precise drug targets. Recent works have uncovered nontraditional roles for
MMPs in the cytosol and nucleus. These have shed light on intracellular targets and biological actions of
MMPs, adding additional layers of complexity for therapeutic
MMP inhibition. In this review, we discussed the recent advances made in understanding nuclear location of
MMPs, their regulation of intranuclear sorting, and their intranuclear proteolytic activity and substrates. In particular, we highlighted the roles of intranuclear
MMPs in oxidative DNA damage, neuronal apoptosis, and
neuroinflammation at an early stage of
stroke insult. These novel data point to new putative
MMP-mediated intranuclear actions in
stroke-induced
pathological processes and may lead to novel approaches to treatment of
stroke and other neurological diseases.