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（差异甲烷）是一种有效的多酚抗氧化剂，抗炎和抗癌化合物，在许多不同的癌症模型中已经经过了广泛的临床前测试，最近又用于创伤性脑损伤，stroke，stroke，stroke，stroke，stroke disementerative疾病，包括来自我们的Alzheimerers（包括我们的AD）（包括我们的AD）（包括我们的AD）。它与AD相关，具有金属螯合和抗淀粉样蛋白聚集活性和功能，可抑制参与淀粉样神经毒性的神经炎性级联反应（AP-1转录）和激酶。基于功效和安全性姜黄素目前正在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相对较差的口服生物利用性，这是由于溶解度差，pH依赖性药物不稳定性和高首先通过葡萄糖代谢而通过羟基代谢而导致的，这是通过在多苯酚中的羟基来代谢。该提案将使用体外筛查和动物模型来解决姜黄素递送问题的可能解决方案，这对于许多有前途的新药是典型的。尽管我们有姜黄素的IND来进行试验临床试验，但由于其出色的安全性概况，但是，改善交付的系统需要重新通用毒性问题。我们将使用阿尔茨海默氏症转基因模型APPSW来评估疗效目标1。使用两种胶束制剂，我们可以大大改善姜黄素的口服吸收。因此，我们将评估姜黄素胶束目标的功效，生物利用度和毒性2。因此，我们将评估姜黄素脂质纳米颗粒的疗效，生物利用度和毒性目标3。姜黄素的主要代谢产物（四氢瓜蛋白，THC）具有出色的口服吸收，并且是一种有效的抗氧化剂。因此，我们将评估天然姜黄素代谢产物（四氢蛋白素）的疗效，生物利用度和毒性4。具有神经保护活性的认知增强姜黄素衍生物（SALK INST）的疗效，可能会进行临床试验，并在短期试验中获得临床试验的迅速批准。姜黄素的衍生物具有脑衍生的神经营养因子（BDNF）的模拟特性具有有效的神经保护性和认知增强特性。因此，我们将检查AppSw小鼠中认知增强BDNF姜黄素衍生物的疗效，生物利用度和毒性。里程碑。第1年。针对生物利用度优化的配方演示（等离子体，红细胞，大脑水平）。第二年。毒理学研究建立了急性安全剂量，剂量反应研究在体内模型中确立了疗效。 3年级。长期（2年）的安全研究完成了姜黄素在长期模型中的单剂量功效。 4年级。姜黄素的剂量反应和行为电池以长期模型完成。准备广告试验临床试验。