Treatment of stroke is limited to a few approved therapeutic options, such as thrombolytic therapy, that have to be administered within rigid short timeframes resulting in the exclusion of many patients. Beyond the this timeframe even fewer effective treatment options exist. Therefore, extending current therapies and developing new treatment options would be highly desirable. Inflammation has been known to extend ischemic brain injury and adversely affect outcome. Although anti-inflammatory therapies can be effective in experimental models, thus far human trials have not shown a clear benefit. While the discrepancy is likely multifactorial, one contributing factor may be related to the use of broad anti-inflammatory agents rather than more focused therapies that target specific molecular pathways and enzymes demonstrated to be deleterious while maintaining the beneficial effects of the inflammatory response. A central obstacle in evaluating and implementing novel anti-inflammatory therapies for stroke is the lack of a noninvasive means to track the evolution of inflammation during stroke to observe the impact of targeted therapies in in vivo animal models and humans. Myeloperoxidase (MPO), a highly oxidizing and damaging enzyme secreted by many activated inflammatory cells, is found abundantly in stroke lesions. We have shown that the MR imaging agent, bis-5HT- DTPA-Gd (MPO-Gd) is highly sensitive and specific for detecting MPO activity. We found that MPO-Gd imaging can report and serially track MPO activity to obtain information that was previously only available from ex vivo studies. MPO-Gd imaging results correlated well with infarct volume and detected MPO activity in the infarct even 21 days post occlusion. In preliminary studies, wild-type mice treated with an MPO inhibitor as well as MPO deficient mice demonstrated substantial decrease in day 21 infarct volume. Therefore, we hypothesize that secreted MPO is a key biomarker for inflammation and infarct propagation, and that reducing MPO activity would improve stroke outcome. The overall goals of this proposal are to study the relationship between MPO and inflammation in stroke evolution and to develop treatment regimens to limit the inflammatory damage by modulating MPO activity/expression and in combination with thrombolytic therapy.
The specific aims are 1) to establish MPO as an imaging biomarker for inflammation in stroke, 2) to assess MPO as a treatment target for stroke, and 3) to determine synergistic treatment regimens between MPO inhibition and thrombolytic therapy. The proposed investigations will provide a platform for the use of MPO molecular imaging in future investigations of basic pathobiology of inflammation in stroke and the impact of novel therapeutic interventions aimed at altering inflammation. Ultimately, the results of this proposal will set the stage for translational projects to benefit stroke patients by providing a noninvasive method to assess the inflammatory status during stroke, improving assessment of novel anti-inflammatory therapies in animals and in humans, and offering a new treatment target for stroke.
Because MPO-Gd is highly stable, nontoxic, and can be used to image MPO activity in a a wide range of clinically important inflammatory diseases, these investigations may provide the basis for application of MPO imaging for diagnostic evaluation of inflammation in humans and MPO inhibition for novel therapeutic interventions to improve outcome in stroke and other diseases.
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