Therapeutic efficacy of metformin in the disease process of EAE

描述（由申请方提供）：本提案的长期目标是评价抗糖尿病药物二甲双胍在多发性硬化症（MS）复发/缓解（RR）模型和慢性动物模型中的临床前转化潜力。目前的建议是基于两个新的最近发表的关键发现：1。AMP活化蛋白激酶（AMPK）是一种能量感应代谢开关，在EAE疾病期间在免疫细胞中下调。2.二甲双胍是AMPK的激活剂，也是众所周知的代谢紊乱药物，由于其抗炎特性，在RR（SJL/J）和慢性（C57 B6）MS小鼠模型中提供了预防功效。对于任何药物的转化潜力，重要的是在相关动物模型表现出临床症状时检查其疗效。在本研究中，我们建议将二甲双胍在RR和EAE疾病慢性模型中的治疗潜力作为临床前研究。我们提出的目的是：1）研究二甲双胍对RR疾病过程和EAE慢性模型的治疗作用。为了检查二甲双胍作为MS患者的药物，二甲双胍在疾病发作时必须显示其有效性。因此，在本研究中，我们计划进行详细研究，以检查当动物显示疾病临床体征时二甲双胍在RR和MS慢性小鼠模型中的治疗作用。2)通过二甲双胍和溶剂处理的EAE的CNS组织的病理学和生物化学分析验证二甲双胍的治疗保护作用。在此目标下，我们建议检查病理学（炎症状态、单核细胞浸润、脱髓鞘和轴突丢失）和代谢紊乱（AMPK活性、脂质谱和脂肪酸组成）作为CNS参数，以评价治疗剂量的二甲双胍在两种EAE模型中的作用。这项研究的新奇是评估使用具有直接翻译意义的抗糖尿病药物治疗MS的可能性。如果成功的话，二甲双胍可以成为一种首选药物，因为它具有良好的生物利用度，并且可以口服，这可以减少治疗费用，频繁的医生访问和痛苦的药物给药。我们的初步数据对临床研究有很大的意义，并提供了单独或与MS和其他神经炎性疾病的现有疗法相结合开发有效疗法的可能性。 公共卫生相关性：多发性硬化症（MS）是一种慢性脑部疾病，主要影响年轻人在他们最富有成效的岁月。MS没有治愈或治疗方法。然而，许多药物可用于治疗疾病，如皮质类固醇，干扰素-1B（Betaseron），干扰素-1（Avonex）和共聚物1。我们建议在EAE动物模型中检查二甲双胍（一种广泛使用的糖尿病药物）。我们的初步数据显示，这种糖尿病药物也可能是治疗MS的药物。在这项工作中，我们将用二甲双胍治疗已经显示出疾病迹象的小鼠，以观察与MS患者治疗的相关性。二甲双胍具有抗炎、抗氧化、恢复内皮功能、激活体内能量调节酶（AMP活化蛋白激酶）等多种特性，且无副作用。最有趣的是，它具有良好的生物利用度，因此二甲双胍口服给药可以减少治疗费用，频繁的医生访问和痛苦的药物管理。如果二甲双胍显示出令人鼓舞的结果，它将对临床研究产生重大影响，并可能发展成为一种有效的治疗方法，单独或与目前的MS治疗联合使用。 免责声明：请注意，以下评论是由审查员在研究部分会议之前准备的，并且以基本上未经编辑的形式提供。 虽然审查人员有机会根据小组讨论情况更新或修订其书面评价，但不能保证在会议讨论之后更新了个人评论。 因此，这些评论可能并不完全反映小组讨论结束时单个评审员的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是评审员在会议上实际认为关键的最后一句话。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to evaluate the preclinical translational potential of anti-diabetic drug, metformin, in the relapsing/remitting (RR) model and chronic animal models of multiple sclerosis (MS). The present proposal is based on the two novel recently published key findings: 1. AMP-activated protein kinase (AMPK), an energy sensing metabolic switch, is down regulated in immune cells during EAE disease. 2. Metformin, an activator of AMPK and well known drug for metabolic disorder, provided prophylactic efficacy in RR (SJL/J) and chronic (C57B6) mouse models of MS due to its anti-inflammatory properties. For translational potential for any drug, it is important to examine its efficacy in relevant animal model(s) when they exhibit clinical symptoms. In the present study we propose to examine the therapeutic potential of metformin in RR and chronic models in EAE disease as a pre-clinical study. We propose aim: 1) To examine the therapeutic effect of metformin in the disease process of RR and chronic models of EAE. To examine metformin as a drug for MS patients, it is important that metformin has to show its effectiveness when given at disease onset. Therefore, in this study we have planned detailed study to examine the therapeutic effect of metformin in RR and chronic mouse models of MS when animals show clinical sign of disease. 2) Validation of therapeutic protection of metformin by pathological and biochemical analysis of CNS tissues of metformin- and vehicle treated EAE. Under this aim, we propose to examine the pathology (status of inflammation, infiltration of mononuclear cells, demyelination and axonal loss) and metabolic derangement (activity of AMPK, lipid profile and fatty acid composition) as a parameter in CNS to evaluate the effect of therapeutic doses of metformin in both EAE models. The novelty of this study is to evaluate a possibility of using anti-diabetic drug for MS that has a direct translational implication. If successful, metformin can be a drug of choice as it has good bioavailability and is given orally which may cut down the cost of therapy, frequent doctor visits and painful administration of drugs. Our preliminary data promises great implications for clinical research and offers the possibility of developing effective therapy alone or in combination with existing therapies for MS and other neuro-inflammatory diseases. Public Health Relevance: Multiple Sclerosis (MS) is a chronic disease of the brain, which affects mostly young adults during their most productive years. There is no cure or treatment available for MS. However, number of medications can be used to treat the disease symptomatically such as corticosteroids, Interferonss-1B (Betaseron), Interferonss-1¿ (Avonex) and Copolymer 1. We propose to examine here, metformin (a widely used drug for diabetes) in animal model of EAE. Our preliminary data shows some promise, that this diabetic drug may be a drug for MS too. In this work we will treat mice with metformin when they already show sign of disease, to see the relevance to MS patient therapy. Metformin has so many properties like anti-inflammatory, anti-oxidant, restore endothelial functions and activates enzyme which regulates energy in body (AMP-activated protein kinase), without many side effects. Most interestingly, it has good bioavailability, so metformin is given orally which may cut down the cost of therapy, frequent doctor visits and painful administration of drugs. If metformin shows encouraging results, it will have great implications for clinical research and may offer the possibility of developing into an effective therapy alone or in combination with current therapy for MS. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.