Anti-inflammatory actions of the natural plant product, Honokiol

描述（由申请人提供）：Honokiol （HNK）是木兰植物的叶子和根茎的天然提取物，长期以来在传统亚洲医学中用于治疗血栓和胃肠道疾病。为了确定HNK是否具有抗炎特性，我们在炎症性类风湿关节炎（RA）小鼠模型中测试了它的作用。我们的初步研究表明，体内炎症和疾病进展以及体外促炎细胞因子的产生和细胞活化都被显著抑制，而没有增加细胞死亡或体内毒性。这些初步研究结果表明，HNK在治疗慢性炎症性疾病（如影响大量人群的类风湿性关节炎）方面具有前景。HNK还抑制通过CD40的信号传导，CD40是一种免疫受体，被认为在RA中起作用，以及ebv编码的CD40模拟物LMP1，被认为与加剧自身免疫性疾病有关。因为HNK有多种抗炎作用，它可能比针对单一分子的治疗更有效。它在传统医学中的长期使用也表明它可以有效而没有危险的副作用。本探索性项目将验证HNK在RA小鼠模型中具有有效抗炎特性的假设，并通过与GABA受体相互作用来减少促炎细胞因子的产生。第一个特异性目的是优化小鼠RA疾病模型的抗炎作用，第二个目的是研究HNK的作用机制。

DESCRIPTION (provided by applicant): Honokiol (HNK) is a natural extract of the leaves and root stems of the Magnolia plant that has long been used in traditional Asian medicine to treat thrombotic and gastrointestinal disorders. To determine if HNK has anti-inflammatory properties, we tested its effects in a mouse model of inflammatory rheumatoid arthritis (RA). Our initial studies show that both in vivo inflammation and disease progression and in vitro pro-inflammatory cytokine production and cellular activation were markedly inhibited, without increased cell death or in vivo toxicity. These preliminary findings suggest that HNK has promise in the treatment of chronic inflammatory diseases such as RA, which affects a large number of people. HNK also inhibited signaling via CD40, an immune receptor that has been implicated as playing a role in RA, as well as an EBV-encoded CD40 mimic called LMP1, that has been implicated in exacerbating autoimmune disease. Because HNK has multiple anti-inflammatory actions, it could prove more effective than treatments targeting a single molecule. Its long prior use in traditional medicine also suggests that it can be effective without dangerous side effects. This exploratory project will test the hypothesis that HNK will have effective anti-inflammatory properties in a mouse model of RA, and that its action will be exerted via interaction with GABA receptors to decrease production of pro-inflammatory cytokines. The first specific Aim will focus on optimizing anti-inflammatory effects in the mouse RA disease model, and the second Aim will examine the mechanism of action of HNK. PUBLIC HEALTH RELEVANCE: This project studies a natural plant product called Honokiol (HNK), which is extracted from plants of the species Magnolia, and has been used for many years as a traditional Asian medicine, without notable toxic side effects. Using controlled studies in a mouse model of human rheumatoid arthritis (RA), our initial work has shown that HNK can inhibit inflammation and progression of the disease. Interestingly, preliminary data indicate that HNK delivers signals to cells through a type of receptor of the nervous system. The current project seeks to build upon these studies to determine the optimal way to use HNK as a treatment for chronic inflammatory disease, and to better understand how HNK exerts its anti- inflammatory effects.