Icariin to Prevent Corticosteroid-Related Memory Changes

描述（由申请人提供）：在动物和人类中，应激和皮质类固醇过量与海马结构和功能的变化有关。这些发现对以下方面具有重要意义：1)情绪障碍患者，因为重度抑郁症和双相情感障碍患者的亚群有皮质醇升高和记忆障碍；2)估计有1%的人接受处方皮质类固醇治疗医学疾病。淫羊藿中的一种黄酮类化合物淫羊藿苷（Icariin）， 1)阻断皮质激素诱导的原代培养大鼠海马神经元凋亡的作用，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，4)在抑郁症动物模型中具有抗抑郁作用。尽管这些有希望的临床前研究结果，以及淫羊藿苷在非处方补充剂中的广泛使用，但没有研究调查过这种化合物对人类大脑的影响，也没有研究过它在人类体内的药代动力学。迄今为止，仅报道了一例淫羊藿苷人体对照试验。在这份报告中，淫羊藿苷似乎是安全的，耐受性良好，有效的，当给予妇女骨质流失。我们小组有一个研究项目，使用在医疗机构接受处方皮质类固醇（如强的松）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作为模型，探索皮质醇升高对人类大脑的影响。我们目前工作的一个主要焦点是研究可能阻断压力或皮质类固醇对海马体（大脑中对记忆至关重要的区域）影响的药物。我们已经确定了几个有前途的代理商。我们建议探索淫羊藿苷是否会阻断氢化可的松（皮质醇）对健康对照者记忆的影响。目前的提议分为两个阶段。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其他与淫羊藿苷有关的人体研究提供所需的数据。在第二阶段，我们将使用我们的范例确定淫羊藿苷是否阻断皮质类固醇对记忆的影响。本实验将通过一系列认知测试和情绪评估，在健康对照中检测淫羊藿苷单独使用和与氢化可的松联合使用。安全性和耐受性也将被监控。一个经验丰富的研究团队，已经完成并发表了与当前提案类似的设计研究，将进行该项目。

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.