Ursolic acid: a novel oral therapy for chronic stage of MS/EAE by both immunomodulation and neural repair

中枢神经系统（CNS）的炎性脱髓鞘和轴突损伤是其特征 多发性硬化（MS）慢性期及其动物模型，实验性自身免疫性 脑脊髓炎（EAE）。目前的MS药物主要是免疫调节，几乎没有效果 对受损CNS组织的神经再生;因此，它们仅在急性期有效， 疾病的慢性阶段。具有免疫调节和神经再生作用的MS疗法 会非常有益这一目标可以通过使用天然三萜类化合物熊果酸（UA）来实现 一种在植物中发现的化合物，广泛存在于人类饮食和抗炎药物中 草药最近发现UA可以抑制几种类型的炎症性疾病，并预防EAE 当在疾病发作前腹膜内注射时，通过抑制Th 1/Th 17细胞分化。此外，保护 神经元凋亡。我们首次发现口服UA可有效抑制持续性EAE 当在EAE的急性和慢性阶段开始治疗时，并促进脑中的髓鞘再生， 切片培养此外，UA治疗显著提高了核因子IL-3（NFIL 3）的表达， 具有免疫调节和神经修复能力的转录因子，以及缺乏NFIL 3 表达大大降低UA效应。 该建议的中心假设是，UA是一种新型的慢性MS/EAE口服疗法， 其免疫调节和直接神经再生的双重作用，通过NFIL 3诱导 机制等提出了三个具体目标来检验这一假设。从学术角度看， 我们致力于研究UA/NFIL 3作用机制的具体目标1和2， 免疫调节和神经修复。从治疗的角度来看，我们将在具体的 目的3探讨尿酸对慢性进展型和复发型慢性前列腺炎的治疗作用。 缓解期（RR）EAE。此外，长期口服UA的潜在副作用和安全性问题也将在 密切监视。 该项目，如果成功，将提供证据表明，UA具有很大的潜力，作为一种口服抗- 用于MS的炎症和神经修复剂，特别是在慢性阶段， 没有有效的治疗。

Inflammatory demyelination and axonal damage of the central nervous system (CNS) are hallmarks of the chronic stage of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Current MS medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged CNS tissue; they are thus only effective in the acute, but not the chronic stage of disease. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. This goal could be achieved by using ursolic acid (UA), a natural triterpenoid compound found in plants that are widely present in the human diet and in anti-inflammatory medicinal herbs. UA has been recently found to inhibit several types of inflammatory diseases and to prevent EAE when i.p. injected before disease onset, by inhibiting Th1/Th17 cell differentiation. UA also protects neurons from apoptosis. We, for the first time, show that oral UA effectively suppresses ongoing EAE when treatment is started at both acute and chronic stages of EAE, and promotes remyelination in brain- slice culture. Further, UA treatment significantly elevates expression of nuclear factor IL-3 (NFIL3), a transcription factor that has both immunomodulatory and neuroreparative capacities, and lack of NFIL3 expression largely reduces UA effects. The central hypothesis of this proposal is that UA is a novel oral therapy for chronic MS/EAE thanks to its dual effects of immunomodulation and direct neuroregeneration, through NFIL3-induced mechanisms. Three specific aims are proposed to test this hypothesis. From the academic perspective, we have dedicated Specific Aims 1 and 2 to investigation of the mechanisms of UA/NFIL3 action in immunomodulation and neural repair, respectively. From the therapeutic perspective, we will in Specific Aim 3 test the therapeutic effects of UA on the chronic stage of chronic-progressive (CP) and relapsing- remitting (RR) EAE. In addition, potential side effects and safety issues of long-term oral UA will also be closely monitored. This project, if successful, will provide evidence that UA has great potential as an oral anti- inflammatory and neural repair agent for MS, especially at the chronic stage, for which there is currently no effective therapy.