Matrix metalloproteinase proteolysis after stroke : a surrogate indicator for early diagnosis and validation of treatment

Matrix metalloproteinases (MMPs) are a family of endoproteaseses that have various functions from development to disease. They are also believed to play critical roles in the central nerve system for the pathogenesis of stroke. In ischemic stroke, MMP 9 is involved in neuronal apoptosis, edema, and hemorrhagic transformation. In stroke models, MMPs degrade ECM components and disrupt neurovascular integrity, resulting in blood-brain barrier (BBB) disruption and hemorrhage which further damage to the ischemic area. There are experimental pharmacological treatments with MMP inhibitors that decrease the extent of neuronal apoptosis and hemorrhage. Recently we tested a new class of mechanism-based MMP-9 specific inhibitors SB-3CT. Our hypothesis is that MMP-9 causes proteolytic changes resulting in neurovascular damage after focal cerebral ischemia in mice. Inhibition of MMP proteolysis with SB-3CT, should result in decreased apoptosis of neurons and improved behavioral outcomes."Supported in part by the grants of NIH/NIEHS&NCCAM, Dana Foundation, AHA to Z.G.

Mechanism-based Inhibitor of Matrix Metalloproteinase-9 Rescues Brain from Focal Cerebral Ischemia-induced Damage and Improve Neurological Outcomes in Mice [abstract]

Neuroscience - Vision & Functional Brain Imaging Poster SessionStroke is the third leading cause of death in the US and the primary cause of long-term disability. Acute ischemic stroke, the most common form of stroke, is caused by clotting in the cerebral arteries leading to brain oxygen deprivation and cerebral infarction. The events involved in stroke include brain cell injury or death, breakdown of the blood-brain barrier (BBB), edema, and hemorrhage, which are associated with the expression and activation of matrix metalloproteinases (MMPs), particularly MMP-9. In two focal cerebral ischemia paradigms - the filament-induced transient middle cerebral artery occlusion (MCAo) and the embolus-induced permanent MCAo in mice, we examined MMP-9 proteolysis of extracellular matrix (ECM) components and the neuroprotective effects of the highly selective mechanism-based inhibitor of MMP-9, SB-3CT, which is activated by MMP-9 under pathological conditions. We demonstrated that MMP-9 degrades the ECM protein laminin and that this degradation induces neuronal apoptosis in a transient focal cerebral ischemia model in mice. SB-3CT dramatically blocks MMP-9 activity and decreases MMP-9-mediated laminin cleavage, thus rescuing neurons from apoptosis and ameliorating neurobehavioral outcomes. Significant therapeutic activity of SB-3CT is seen up to 6 h after initial brain damage. Moreover, treatment with SB-3CT attenuates brain MMP-9 activity and protects against delayed neuronal cell death in the embolus-induced permanent MCAo in mice. We conclude that MMP-9 is a highly promising drug target and that SB-3CT has significant therapeutic potential in stroke patients

A mouse model of embolic focal ischemic stroke for investigation of anti-thrombotic therapies

Title from PDF of title page (University of Missouri--Columbia, viewed on November 3, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Thesis advisor: Dr. Zezong Gu.M. S. University of Missouri--Columbia 2010.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Stroke is the third leading cause of death in the United States and the major cause of adult disability. Ischemic stroke accounts for about 87 percent of all cases, and is a condition in which there is insufficient blood flow and poor oxygen supply to the brain to meet metabolic demand, thus causing complex pathophysiology and damage to neurons and glial cells. Release of excitatory neurotransmitters such as glutamate and activation of ionotropic glutamate receptors such as that mediated by N-methyl-D-aspartic acid (NMDA) contribute to influx of calcium and stimulation of a train of events leading to mitochondrial dysfunction and neuronal apoptosis. Ischemia also triggers activation of matrix metalloproteinases (MMPs), known to play a role in degradation of extracellular matrix and disruption of blood brain barrier (BBB) and induction of neuronal cell death. Even though there are several models to mimic the effects of ischemic stroke, the embolic focal cerebral ischemic model is unique and one representing the most relevant physiological changes of ischemic stroke in human. Therefore, this embolic ischemic model may be used to identify the ischemia/stroke-induced brain damage due to lack of oxygen supply and other physiological stress, and studies to investigate potential drugs or agents for therapeutic purposes.Includes bibliographical references (pages 82-87)