Curcumin and Curcumin Derivatives for Alzheimer's

姜黄素和姜黄素衍生物治疗阿尔茨海默病

• 批准号: 7134394
• 负责人: SALLY ANN FRAUTSCHY
• 金额: $ 21.82万
• 依托单位: SEPULVEDA RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7134394
• 关键词: Alzheimer' s disease; antiinflammatory agents; antioxidants; biological products; biomimetics; brain derived neurotrophic factor; cooperative study; dosage; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; genetically modified animals; laboratory mouse; micelles; nanomedicine; neuroprotectants; pharmacokinetics; toxicology

DESCRIPTION (provided by applicant): Curcumin (diferulomethane) is a potent polyphenolic antioxidant, anti-inflammatory and anticarcinogenic compound that has gone through extensive pre-clinical testing in many different models for cancer and more recently for traumatic brain injury, stroke and other neurodegenerative diseases including work from our lab on Alzheimer's (AD). Relevant to AD, it has metal chelating and anti-amyloid aggregation activity and functions to inhibit the neuroinflammatory cascade (AP-1 transcription) and kinases involved in amyloid neurotoxicity. Based on efficacy and safety curcumin is currently in clinical trials for cancers and Alzheimer's, but the major issue that may limit its potential is relatively poor oral bioavailablity caused by poor solubility, pH dependent drug instability and high first pass metabolism through glucuronidation of the hydroxyls in the polyphenols. This proposal will use in vitro screens and animal models to address possible solutions to these problems with curcumin delivery, which are typical for many promising new drugs. Although we have an IND for curcumin for our pilot clinical trial, because of its excellent safety profile, systems of improved delivery need to re-address toxicity issues. We will use the Alzheimer transgenic model APPsw to evaluate efficacy Aim 1. We can greatly improve oral absorption of curcumin, using two preparations of micelles. Therefore we will evaluate the efficacy, bioavailability and toxicity of curcumin micelles Aim 2. Nanoparticles technology is becoming useful tools for improving the delivery of strongly hydrophobic drugs. Therefore we will evaluate the efficacy, bioavailability and toxicity of a curcumin lipid nanoparticles Aim 3. The major metabolite of curcumin (tetrahydrocurcumin, THC) has superior oral absorption and is a potent antioxidant. Therefore we will evaluate the efficacy, bioavailability and toxicity of the natural curcumin metabolite (tetrahydrocurcumin) Aim 4. A cognitive enhancing curcumin derivative (Salk Inst) with neuroprotective activity may enter clinical trials and gain approval fairly rapidly in short trials. A derivative of curcumin with brain derived neurotrophic factor (BDNF) mimetic properties has potent neuroprotective and cognitive enhancing properties. Therefore we will examine the efficacy, bioavailability and toxicity of the cognitive enhancing BDNF curcumin derivative in the APPsw mouse. Milestones. Year 1. Demonstration of formulations optimized for bioavailability (plasma, erythrocyte, brain levels). Year 2. Toxicology studies establish acute safety dosing and the dose response studies establish efficacy in acute in vivo models. Year 3. Long term (2 yr) safety studies completed and single dose efficacy for curcumin in long-term models. Year 4. Dose-response and behavior battery for curcumin completed in long-term models. Prepare for AD pilot clinical trial.

描述（由申请人提供）：姜黄素（二阿魏甲烷）是一种有效的多酚抗氧化剂、抗炎和抗癌化合物，已在许多不同的癌症模型以及最近的创伤性脑损伤、中风和其他神经退行性疾病模型中经过了广泛的临床前测试。疾病，包括我们实验室在阿尔茨海默病 (AD) 方面的工作。与 AD 相关，它具有金属螯合和抗淀粉样蛋白聚集活性，并具有抑制神经炎症级联反应（AP-1 转录）和参与淀粉样蛋白神经毒性的激酶的功能。基于功效和安全性，姜黄素目前正处于癌症和阿尔茨海默氏症的临床试验中，但可能限制其潜力的主要问题是由于溶解度差、pH 依赖性药物不稳定以及通过羟基葡萄糖醛酸化的高首过代谢而导致口服生物利用度相对较差。多酚。该提案将使用体外筛选和动物模型来解决姜黄素输送这些问题的可能解决方案，这对于许多有前途的新药来说是典型的。尽管我们有姜黄素的 IND 用于试点临床试验，但由于其出色的安全性，改进的输送系统需要重新解决毒性问题。我们将使用阿尔茨海默病转基因模型APPsw来评估功效目标1。我们可以使用两种胶束制剂极大地改善姜黄素的口服吸收。因此，我们将评估姜黄素胶束的功效、生物利用度和毒性。目标2。纳米颗粒技术正在成为改善强疏水性药物递送的有用工具。因此，我们将评估姜黄素脂质纳米粒的功效、生物利用度和毒性。目标3。姜黄素的主要代谢物（四氢姜黄素，THC）具有优异的口服吸收性，是一种有效的抗氧化剂。因此，我们将评估天然姜黄素代谢物（四氢姜黄素）的功效、生物利用度和毒性。目标4。具有神经保护活性的认知增强姜黄素衍生物（Salk Inst）可能会进入临床试验，并在短期试验中相当快地获得批准。姜黄素衍生物具有脑源性神经营养因子 (BDNF) 模拟特性，具有有效的神经保护和认知增强特性。因此，我们将检查认知增强 BDNF 姜黄素衍生物在 APPsw 小鼠中的功效、生物利用度和毒性。里程碑。第一年。演示针对生物利用度（血浆、红细胞、脑水平）进行优化的配方。第 2 年。毒理学研究确定急性安全剂量，剂量反应研究确定急性体内模型的功效。第三年。长期（2 年）安全性研究已完成，姜黄素在长期模型中的单剂量疗效已完成。第四年。在长期模型中完成姜黄素的剂量反应和行为电池。为 AD 试点临床试验做好准备。