Role of neutrophil Matrix Metalloproteinase-9 in exacerbation of blood brain barrier disruption and brain injury following ischemic stroke
Introduction. Stroke is an acute neurological syndrome that arises as a result of reduced blood flow to the central nervous system. The resulting ischemic necrosis of nervous tissue frequently leads to death or severe long-term disability1. Despite rising incidence of ischemic stroke around the world, there is still a profound lack of treatment options available outside of thrombolysis or thrombectomy2. However, there are still many promising targets for the development of stroke therapies. Studies have indicated that a significant driver of damage in the post-stroke microenvironment is blood-brain barrier damage. Studies indicate that one significant source of this damage is neutrophil-derived matrix metalloproteinase-9 (MMP-9)3. Finding a method to prevent neutrophil infiltration or matrix metalloproteinase-9 release after stroke therefore is a potential therapy for treatment of ischemic stroke. Methods. A systematic review of the current literature was performed to examine the feasibility of neutrophil-derived matrix metalloproteinase-9 as a therapeutic target in stroke. Multiple animal studies were examined to assess the role MMP-9 has in blood-brain barrier damage, hemorrhagic transformation and functional deficit after stroke. Results. MMP-9 knockout mice show significantly increased cerebral swelling, cerebral hemorrhage, and infarction size in a stroke model when compared to MMP-9 positive animals4. Similar effects were seen in animals treated with injections of regulatory T cells after cerebral artery occlusion5. The effects of reducing neutrophil infiltration produced similar results in multiple studies with reduced edema and infarct volumes being observed when neutrophil recruitment was attenuated6,7. Conclusions. Neutrophils are one of the first infiltrating immune cells in the context of ischemia stroke. There is a large body of evidence that this response causes great deal of damage after stroke. Review of the literature shows that a significant contributor to this process is matrix metalloproteinase-9. Inhibition of neutrophil recruitment, knockout of matrix metalloproteinase-9 and inhibition of MMP-9 expression all show similar improvements in stroke outcomes. This indicates that neutrophil modulation and more specifically matrix metalloproteinase-9 inhibition represent promising targets for improving functional outcomes after stroke.
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