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相关。这些发现对1）情绪障碍患者具有重要意义，因为患有重度抑郁症和双相情感障碍的人的子集具有升高的皮质醇和记忆障碍，以及2）估计1%的人口接受处方皮质类固醇治疗医学疾病。淫羊藿苷，一种来自淫羊藿的类黄酮，1）阻断原代培养的大鼠海马神经元中皮质类固醇诱导的细胞凋亡的作用，2）在缺血的动物模型中是神经保护性的，3）在认知的动物模型中改善记忆，和4）在抑郁症的动物模型中具有抗抑郁特性。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可用性，但没有研究检查这种化合物对人脑的影响或检查其在人体中的药代动力学。迄今为止，只有一项关于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，耐受性良好，有效的妇女时，给予骨质流失。我们小组有一个研究项目，使用接受处方皮质类固醇（如泼尼松）治疗的医疗环境中的患者或在实验室范式中接受短暂皮质类固醇暴露的健康对照作为模型，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重点是药物，可能会阻止压力或皮质类固醇对海马体（大脑区域的记忆至关重要）的影响。我们已经确定了几个有前途的代理人。我们建议探讨淫羊藿苷是否会阻止氢化可的松（皮质醇）对健康对照记忆的影响。目前的建议分为两个阶段。在I期，将评估淫羊藿苷的药代动力学以及两种剂量的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其他未来的人类研究提供所需的数据。在第二阶段，我们将确定淫羊藿苷是否阻断皮质类固醇对记忆的影响，使用我们的范例。该实验将使用认知测试和情绪评估的电池在健康对照中检查单独的淫羊藿苷和与氢化可的松的组合。还将监测安全性和耐受性。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本提案中类似设计的研究。

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.