The objectives of this application are to address the effects and mechanisms of postischemic reperfusion in the development of Hemorrhage transformation (HT) and to examine the feasibility of peroxynitrite decomposition catalytic and peptide-protein matrix metalloproteinase (MMP) inhibitor treatment. These studies are closely related to the hemorrhage complication from mechanical recanalization during the treatment of stroke patients. Although it has been known that prolonged ischemia is important in the development of HT, the role of reperfusion itself on HT and related mechanisms has not been well studied. Even in cases of transient MCAO, activated MMP-2 or MMP-9 was not detected in some research groups. Our hypothesis here is that: 1) Reperfusion, after prolonged ischemia, accelerates and potentiates MMP activation relative to permanent ischemia, that worsens intracerebral HT. 2) Peroxynitrite formation during reperfusion contributes to MMP activation. 3) The decomposition of peroxynitrite or the blocking MMP activity by using peptide-protein MMP inhibitors just before reperfusion will prevent or decrease the injury to the neurovascular unit and HT.
Our specific aims are to: 1) Define the relationship between reperfusion, peroxynitrite, and MMP activation. We will determine: a) whether reperfusion potentiates MMP activation (MMP subtypes) by using both pharmacological method and MMP knockout mice;b) whether peroxynitrite formation during reperfusion contribute to MMP activation and effect of FeTMPyP (a peroxynitrite decomposition catalyst) and c) whether administration of peptide-protein MMP inhibitors just before reperfusion can pass blood brain barrier and which of them is most effective. 2) Assess the effects of FeTMPyP or peptide-protein MMP inhibitors (administered just before reperfusion) and MMP knockout on neurovascular injury. 3) Determine if reperfusion after pronged ischemia worsens HT and whether administering FeTMPyP or a peptide/protein MMP inhibitor just before reperfusion decreases intracerebral hemorrhage. An anti-MMP9 neutralized monoclonal antibody, a cyclic peptide inhibitor of MMP-2 and -9, AHA (a tetrapeptidyl hydroxamic acid, MMP-1, -3, -8 and -9 inhibitor), TIMP-1 and FeTMPyP will be tested. Each of these compounds has potential for clinical use. Since administering protective drugs just before reperfusion is the most practicable clinical time point for preventing HT, these studies are important.
The objectives of this application are to address the effects and mechanisms of postischemic reperfusion in the development of intracerebral hemorrhage and to examine the feasibility of peroxynitrite decomposition catalyst (PDC) and peptide-protein matrix metalloproteinase (MMP) inhibitor treatment. These studies are closely related to the prevention of the hemorrhage complication from mechanical recanalization during the treatment of stroke patients.
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|Lu, Aigang; Clark, Joseph F; Broderick, Joseph P et al. (2008) Reperfusion activates metalloproteinases that contribute to neurovascular injury. Exp Neurol 210:549-59|