Jeremy Maylath

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 attenuated^6,7. 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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