SAFETY AND BETA-HCG + ERYTHROPOIETIN IN ACUTE STROKE

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stroke remains a major source of human morbidity and mortality. Stroke is the third leading cause of death in the Western countries, with approximately 1 in 15 deaths attributable to stroke, and the second leading cause of death worldwide. Approximately 85% of patients survive an acute stroke, living an average of seven years thereafter. Most are left with significant disability1-3, which reduces activities and participation. Stroke most frequently is caused by an ischemic infarct due to thromboembolic cerebral artery occlusion and, thus, can affect all aspects of brain function. The nature and severity of post-stroke deficits vary widely. Over the weeks-months following a brain infarction, most patients do show some spontaneous improvement in those behaviors affected by stroke4-6. However, this recovery is highly variable and generally incomplete. As a result, stroke is the leading cause of adult disability in the U.S. and many other countries. Currently approved stroke therapies are focused on hyperacute interventions (within 6-8 hours after onset) and aim to salvage threatened tissue. A range of prior animal studies suggest that behavioral gains can also be achieved by introducing a neurotrophic therapy within the first few days after stroke7-9. Importantly, such an approach allows a time window for intervention that is measured in days rather than hours. Preclinical studies using the therapeutic regimen proposed herein also support the potential to improve outcome with this approach. Such interventions are thought to derive gains from a neurotrophic mechanism, i.e., the intervention does not reduce the volume of infarct, but instead promotes recovery-related brain events10-17. Increasing investigation has explored the neurobiology of spontaneous post-stroke recovery in part because of the hope to use this information to develop strategies to improve patient outcomes18-20. A number of changes arise in the brain over the weeks following a stroke. These have been described at multiple levels in experimental models of stroke in laboratory animals. Cellular and molecular studies in animals undergoing an experimental unilateral infarct have characterized ion and neurotransmitter changes, changes in cortical excitability, inflammation, angiogenesis, neurogenesis, synaptogenesis, and cellular growth, many of which evolve bilaterally, during the days to weeks that follow a unilateral insult21. A body of evidence supports the idea that many of these events contribute to spontaneous recovery of function after a stroke in humans, too17, 18, 22-26. Furthermore, exogenous interventions have been found that in experimental animal models of stroke amplify these molecular events and simultaneously improve behavioral outcome. Examples include amphetamine12, growth factors8, 27, cellular therapies28, 29, brain stimulation30-32, increased environmental complexity33, 34, and increased physical activity level10. Thus, there are discrete molecular brain events that arise in the days following an infarct, these brain events likely underlie or substantially contribute to spontaneous recovery, and in animals these events can be therapeutically augmented in association with improved behavioral outcome. These events are the target of the current therapeutic intervention whose safety will be assessed in the proposed study.