ISCHEMIC CONDITIONING AS A NEURORECOVERY AGENT FOR STROKE

 描述（由申请人提供）：康复是改善卒中后功能和减少残疾的少数选择之一，但康复训练通常不能恢复卒中后功能。因此，迫切需要找到一种有效的药物，当与康复训练配对时，将促进学习的神经生物学过程，并将大大改善人类中风的结果。缺血性条件反射就是这样一种有前途的药物。缺血性条件反射是一种内源性现象，其中将靶器官或另一种远端器官或组织暴露于一次或多次短暂的亚致死性缺血发作导致靶器官免受缺血。一种临床上可行的方法是远程肢体缺血调节（RLIC），其中缺血和再灌注的发作是由血压袖带引起的。在人类中，RLIC的心脏保护作用已被反复证明，而神经保护作用才刚刚开始评估。在这里，我们提出RLIC的多因素，表观遗传机制可能超出心脏和神经保护，并进入可塑性，学习和恢复。基于可靠的初步数据，我们的中心假设是RLIC的多因素机制可以作为神经恢复剂来提高卒中康复和结局。目前的提议旨在收集将这种有希望的干预措施沿着翻译途径转移所需的关键信息。在这个第一阶段的项目中，我们将提供RLIC通过循环的充气和放气的血压袖带的上臂。我们将比较RLIC +培训与假条件+培训，在200名神经系统完整的成年人，在各种实验操作。目标1将确定RLIC促进哪些类型的康复训练。 目的2通过评价诱导RLIC所需的袖带压力、RLIC的剂量-反应特性和滞留效应，优化RLIC方案，并探索潜在的RLIC血清标志物。目标3将通过研究有和无特定合并症的中老年患者以及临床前文献中已确定和/或卒中后常见的药物来确定RLIC应答者的关键特征。最后，目标4将探索在中风后的前几周内在15人中使用RLIC +训练的可行性。该项目的结果将提供必要的数据，以最大限度地提高中风患者II期随机对照试验的设计。RLIC相对于其他潜在的中枢神经系统预充选项的主要优点是其简单的技术、低成本和临床可行性。虽然我们的初始转化目标是中风，但RIC的潜在受益远远超出中风，扩展到其他神经和老年（例如平衡和福尔斯）康复人群。

 DESCRIPTION (provided by applicant): Rehabilitation is one of the few options to improve function and reduce disability after stroke, but rehabilitation training cannot typically restore pe-stroke function. Thus, there is an urgent need to find an effective agent that, when paired with rehabilitation training, will facilitate the neurobiological processes of learning, and will substantially improve human stroke outcomes. Ischemic conditioning is one such promising agent. Ischemic conditioning is an endogenous phenomenon in which exposing a target organ or another, remote organ or tissue to one or more brief episodes of sub-lethal ischemia results in protection of the target organ against ischemia. A clinically-feasible method is remote limb ischemic conditioning (RLIC), where episodes of ischemia and reperfusion are induced with a blood pressure cuff. In humans, the cardioprotective effects of RLIC have been demonstrated repeatedly, while neuroprotective effects are just beginning to be evaluated. Here, we propose that the multifactorial, epigenetic mechanisms of RLIC might extend beyond cardio- and neuroprotection and into plasticity, learning, and recovery. Based on robust preliminary data, our central hypothesis is that the multifactorial mechanisms of RLIC can be harnessed as a neurorecovery agent to enhance stroke rehabilitation and outcomes. The current proposal is designed to gather the critical information needed to move this promising intervention down the translational pathway. In this Phase I project, we will deliver RLIC via cycles of inflation and deflation of a blood pressure cuff to the upper arm. We will compare RLIC + training vs. sham conditioning + training, in 200 neurologically- intact adults, in various experimental manipulations. Aim 1 will determine which types of rehabilitation training are facilitated by RLIC. Aim 2 will optimize the RLIC protocol by evaluating the necessary cuff-pressures to induce RLIC, the dose-response properties and retention effects of RLIC, and explore potential serum markers of RLIC. Aim 3 will identify key characteristics of responders to RLIC by studying middle-aged and older adults with and without specific co-morbidities and medications that have been identified in the preclinical literature and/or are common post stroke. Finally, Aim 4 will explore the feasibility of using RLIC + training in 15 people within the first few weeks after stroke. Outcomes from this project will provide the necessary data to maximize the design of a Phase II randomized, controlled trial in persons with stroke. A major advantage of RLIC over other potential central nervous system priming options is its simple technology, low cost, and clinical feasibility. While our initial translational target is stroke, the potential benefits of RIC extend far beyond stroke to other neuro- and geriatric (e.g. balance and falls) rehabilitation populations.