Curcumin and Curcumin Derivatives for Alzheimer's

描述（由申请人提供）：姜黄素（二维甲烷）是一种有效的多酚类抗氧化剂，抗炎和抗癌化合物，已在许多不同的癌症模型中进行了广泛的临床前测试，最近用于创伤性脑损伤，中风和其他神经退行性疾病，包括我们实验室对阿尔茨海默氏症（AD）的研究。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）和淀粉样蛋白神经毒性相关激酶的功能。基于疗效和安全性，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度，这是由于溶解度差，pH依赖的药物不稳定性以及通过糖醛酸化多酚中的羟基的高首过代谢引起的。该提案将使用体外筛选和动物模型来解决姜黄素输送的这些问题，这是许多有前途的新药的典型问题。虽然我们有姜黄素的IND用于我们的试点临床试验，但由于其良好的安全性，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来评估疗效。使用两种胶束制剂可以大大提高姜黄素的口服吸收。因此，我们将对姜黄素胶束的有效性、生物利用度和毒性进行评价。纳米颗粒技术正在成为改善强疏水性药物输送的有用工具。因此，我们将评估姜黄素脂质纳米颗粒的功效、生物利用度和毒性。姜黄素的主要代谢产物（四氢姜黄素，THC）具有良好的口服吸收，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。一种具有神经保护作用的认知增强姜黄素衍生物（Salk Inst）可能很快进入临床试验并在短期内获得批准。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，我们将研究认知增强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。年1。优化生物利用度（血浆、红细胞、脑水平）的配方演示。第二年。毒理学研究建立了急性安全性给药，剂量反应研究建立了急性体内模型的有效性。年3。长期（2年）安全性研究完成，长期模型中姜黄素单剂量有效性研究。年4。姜黄素的剂量-反应和行为电池在长期模型中完成。准备AD中试临床试验。

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.