Matrix metalloproteinases and ADAMs in stroke

Abstract

Stroke is a leading cause of death and disability worldwide. However, after years of in-depth research, the pathophysiology of stroke is still not fully understood. Increasing evidence shows that matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinase" (ADAMs) participate in the neuro-inflammatory cascade that is triggered during stroke but also in recovery phases of the disease. This review covers the involvement of these proteins in brain injury following cerebral ischemia which has been widely studied in recent years, with efforts to modulate this group of proteins in neuroprotective therapies, together with their implication in neurorepair mechanisms. Moreover, the review also discusses the role of these proteins in specific forms of neurovascular disease, such as small vessel diseases and intracerebral hemorrhage. Finally, the potential use of MMPs and ADAMs as guiding biomarkers of brain injury and repair for decision-making in cases of stroke is also discussed.

Keywords: ADAM; Biomarker; MMP; Neuroprotection; Neurorepair; Stroke.

Fig. 1

Described roles of MMPs after ischemic stroke. MMP-2 and MMP-14 (MT1-MMP) are the main constitutive enzymes in the brain, expressed principally in astrocytes. MMP-3 and MMP-9 are inducible MMPs in the brain, being mainly produced by resident microglia and infiltrating neutrophils. Moreover, MMP-13 is also involved in the injury cascade, being principally produced by neurons and oligodendrocytes. After the ischemic event, there is an increase in MMPs both in blood and brain, being the most studied ones MMP-9 and MMP-2. These two proteins are thought to be responsible of collagen IV degradation, a major component of the basal lamina, ultimately leading to BBB disruption. BBB blood–brain barrier, MMP matrix metalloproteinase