Icariin to Prevent Corticosteroid-Related Memory Changes

描述(申请人提供)：在动物和人类中，应激和皮质类固醇过量与海马体结构和功能的变化有关。这些发现对1)情绪障碍患者具有重要意义，因为患有严重抑郁障碍和双相情感障碍的人的亚群皮质醇和记忆力受损，以及2)估计有1%的人因内科疾病而接受处方皮质类固醇治疗。淫羊藿苷是淫羊藿黄酮类化合物，1)阻断皮质类固醇诱导的原代培养大鼠海马神经元的凋亡效应，2)在缺血动物模型中具有神经保护作用，3)在认知动物模型中改善记忆，以及4)在抑郁动物模型中具有抗抑郁特性。尽管有这些有希望的临床前发现，而且淫羊藿苷在非处方药补充剂中得到了广泛的应用，但还没有研究检验这种化合物对人脑的影响，也没有研究它在人类体内的药代动力学。到目前为止，只有一次淫羊藿苷的人体对照试验被报道。在这份报告中，淫羊藿苷似乎是安全的，耐受性好，对治疗骨质流失的妇女有效。我们团队有一个研究计划，使用在医疗环境中接受处方皮质类固醇(如泼尼松)治疗的患者或在实验室范例中接受短暂皮质类固醇暴露的健康对照组作为模型，以探索皮质醇升高对人脑的影响。我们目前工作的一个主要焦点是研究可以阻断压力或皮质类固醇对海马体(一个对记忆至关重要的大脑区域)影响的药物。我们已经确定了几个有希望的代理人。我们建议探索淫羊藿苷是否会阻断氢化可的松(皮质醇)对健康对照组记忆的影响。目前的提案分为两个阶段。在第一阶段，将评估淫羊藿苷的药代动力学，以及两种剂量淫羊藿苷的安全性和耐受性。这将为该提案的第二阶段以及未来对淫羊藿苷的其他人类研究提供必要的数据。在第二阶段，我们将使用我们的范例来确定淫羊藿苷是否能阻断皮质类固醇对记忆的影响。这项实验将通过一系列认知测试和情绪评估，在健康对照组中单独检测淫羊藿苷以及与氢化可的松联合使用。安全性和耐受性也将受到监测。一个经验丰富的研究小组将开展该项目，该小组已完成并发表了与当前提案中类似设计的研究报告。

DESCRIPTION (provided by applicant): In animals and humans, stress and corticosteroid excess are associated with changes in hippocampal structure and functioning. These findings have important implications for 1) patients with mood disorders, because subsets of people with major depressive disorder and bipolar disorder have elevated cortisol and memory impairment, and 2) the estimated 1% of the population treated with prescription corticosteroids for medical illnesses. Icariin, a flavonoid from Epimedium, 1) blocks the effects of corticosteroid-induced apoptosis in primary cultured rat hippocampal neurons, 2) is neuroprotective in animal models of ischemia, 3) improves memory in animal models of cognition, and 4) has antidepressant properties in an animal model of depression. Despite these promising pre-clinical findings, and the widespread availability of icariin in over-the-counter supplements, no studies have examined the effects of this compound on the human brain or examined its pharmacokinetics in humans. Only one human controlled trial of icariin has been reported, to date. In this report icariin appeared to be safe, well tolerated and effective when given to women for bone loss. Our group has a research program using patients in medical settings receiving prescription corticosteroid (e.g. prednisone) therapy or healthy controls receiving brief corticosteroid exposures in a laboratory paradigm as models to explore the effects of cortisol elevations on the human brain. A major current focus of our work is on medications that may block the effects of stress or corticosteroids on the hippocampus (a brain region essential for memory). We have identified several promising agents. We propose to explore whether icariin will block the effects of hydrocortisone (cortisol) on memory in healthy controls. The current proposal has two phases. In Phase I the pharmacokinetics of icariin, and the safety and tolerability of two icariin doses wil be assessed. This will provide needed data for the second phase of this proposal, and for other future human research with icariin. In Phase II we will determine whether icariin blocks the effects of corticosteroids on memory using our paradigm. This experiment will examine icariin both alone and in combination with hydrocortisone in healthy controls using a battery of cognitive tests and mood assessments. Safety and tolerability will also be monitored. A highly experienced research team that has completed and published studies with similar designs as in the current proposal will conduct the project.