Banerjee Piu, Wang Yubo, Carnevale Lauren N, Patel Parth, Raspur Charlene K, Tran Nancy, Zhang Xu, Natarajan Ravi, Roberts Amanda J, Baran Phil S, Lipton Stuart A
Neurodegeneration New Medicines Center, Department of Molecular & Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Socrates Biosciences, Inc., Camarillo, CA 93012, USA.
Antioxidants (Basel). 2025 Feb 28;14(3):293. doi: 10.3390/antiox14030293.
The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer's disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as "generally regarded as safe", indicating diAcCA is suitable for human clinical trials in AD.
抗氧化/抗炎化合物肌醇六磷酸（CA）是一种在迷迭香和鼠尾草等草药中发现的酚类二萜。激活后，CA表现出亲电特性，通过与Keap1反应刺激Nrf2转录途径。然而，纯化的CA很容易被氧化，因此高度不稳定。为了将CA开发为阿尔茨海默病（AD）的治疗药物，我们合成了前药衍生物，其中二乙酰化形式（diAcCA）表现出优异的类药物特性。diAcCA在被吸收进入血液之前在胃中转化为CA，并表现出更高的稳定性和生物利用度，以及与CA相当的药代动力学（PK）和疗效。为了测试diAcCA在AD转基因小鼠中的疗效，5xFAD小鼠（或同窝对照）接受该药物治疗3个月，随后进行行为和免疫组织化学研究。值得注意的是，除了淀粉样斑块和tau缠结外，人类AD的一个标志是突触丧失，这是认知衰退的一个主要相关因素。接受diAcCA治疗的5xFAD动物在免疫组织化学分析中显示出突触拯救，同时在水迷宫试验中学习和记忆能力得到改善。diAcCA治疗减少了星形胶质细胞和小胶质细胞炎症、淀粉样斑块形成以及磷酸化tau神经突聚集。在毒性研究中，diAcCA与CA一样安全或更安全，CA被美国食品药品监督管理局列为“一般认为安全”，这表明diAcCA适用于AD的人体临床试验。
