Therapeutic efficacy of metformin in the disease process of EAE

描述（由申请人提供）：本申请的长期目标是评估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。目前的建议是基于最近发表的两个新颖的关键发现：1。amp活化蛋白激酶（AMPK）是一种能量感知代谢开关，在EAE疾病期间免疫细胞中下调。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，二甲双胍对RR （SJL/J）和慢性（C57B6）小鼠MS模型具有预防作用。对于任何药物的转化潜力，当它们表现出临床症状时，在相关动物模型中检查其疗效是很重要的。在本研究中，我们建议在临床前研究中检查二甲双胍在RR和EAE慢性模型中的治疗潜力。我们的目的是：1)探讨二甲双胍在RR和EAE慢性模型疾病过程中的治疗效果。为了检验二甲双胍作为多发性硬化症患者的药物，重要的是二甲双胍必须在疾病发作时显示其有效性。因此，在本研究中，我们计划了详细的研究，当动物出现临床疾病症状时，检验二甲双胍在RR和MS慢性小鼠模型中的治疗效果。2)通过二甲双胍治疗EAE的CNS组织病理和生化分析验证二甲双胍的治疗保护作用。在此目的下，我们建议将病理（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的参数来评估二甲双胍治疗剂量对两种EAE模型的影响。这项研究的新颖之处在于评估使用抗糖尿病药物治疗多发性硬化症的可能性，这具有直接的翻译意义。如果成功，二甲双胍可以作为一种选择药物，因为它具有良好的生物利用度，口服可以减少治疗成本，减少频繁的医生就诊和药物管理的痛苦。我们的初步数据有望对临床研究产生重大影响，并为开发针对多发性硬化症和其他神经炎性疾病的有效治疗方法提供了可能性。

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.