The Role of Adenosine in Ketogenic Diet Therapy

腺苷在生酮饮食疗法中的作用

基本信息

批准号：
8050452
负责人：
Detlev Boison
金额：
$ 42.28万
依托单位：
TRINITY COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8050452
关键词：
Ablation Acute Adenosine Adenosine A1 Receptor Adverse effects Affect Alternative Therapies Anticonvulsants Area Behavioral Behavioral Paradigm Bioenergetics Biogenesis Brain Brain Injuries Brain region Carbohydrates Cells Childhood Chronic Clinical Commit Coupled Data Development Diabetes Mellitus Diet Diet therapy Drug resistance Electrochemistry Electrophysiology (science)Epilepsy Extracellular Space Family Fasting Fatty acid glycerol esters Frequencies Genetic Goals Health Hippocampus (Brain)Human In Vitro Ketone Bodies Ketoses Ketosis Link Measures Mediating Mental disorders Metabolic Metabolism Mitochondria Modeling Mus Mutation Nerve Degeneration Neuraxis Neuromodulator Neurons Neuroprotective Agents Outcome Peripheral Persons Pharmacologic Substance Pharmacological Treatment Population Principal Investigator Prospective Studies Publishing Purinergic P1 Receptors Randomized Rattus Receptor Activation Refractory Regulation Research Research Personnel Rodent Model Role Seizures Severities Signal Transduction Slice Stroke Synaptic Transmission System Techniques Testing Therapeutic Time Transgenic Mice Translating Work age group autocrine base clinically relevant in vivo innovation insight interest ketogenic diet ketogentic nervous system disorder neurochemistry neuronal excitability novel patient population prevent public health relevance receptor research study response sedative success synaptic inhibition

项目摘要

DESCRIPTION (provided by applicant): Epilepsy affects approximately 1% of the population across all age groups and is one of the most prevalent chronic neurological disorders. Unfortunately, current pharmacological treatments do not control seizures adequately in up to 35% of persons with epilepsy. As an alternative, therapy with a high-fat low-carbohydrate (ketogenic) diet can be highly effective in medically-refractory epilepsy, and the mechanisms underlying its success can offer insight into other neurological disorders with metabolic underpinnings. Despite intense interest, key mechanisms underlying the clinically- established anticonvulsant success of ketogenic diet therapy remain unknown. Adenosine, the core molecule of ATP, is an inhibitory neuromodulator that links cell metabolism directly to neuronal activity. Understanding how to regulate adenosine, an endogenous anticonvulsant and neuroprotectant, offers powerful therapeutic benefits. Akin to a ketogenic diet's success with refractory epilepsy, adenosine is an effective anticonvulsant in models of drug- resistant epilepsy. The central hypothesis is that ketogenic diets increase adenosine A1 receptor activation, and that this increased inhibitory influence of adenosine is critical for the anticonvulsant success of ketogenic diet therapy. To test this hypothesis, bioenergetic, neurochemical, electrophysiological and behavioral techniques will be applied after ketogenic diet therapy in rats and mice with normal or genetically-altered adenosine signaling. Experiments using the most accurate bioenergetic and neurochemical techniques will quantify changes in energy molecules, adenosine, adenosine receptors, and ketone bodies (Aim 1). Changes in adenosine's influence on synaptic transmission and neuronal excitability will be quantified using detailed electrophysiology and electrochemistry (Aim 2). Experiments using behavioral paradigms of genetically-based seizures or modeled epilepsy will quantify changes in seizure frequency and severity (Aim 3). Preliminary and published data from others and us support the hypothesis that ketogenic strategies increase levels and actions of adenosine. The proposed experiments will measure levels of adenosine and test the role of adenosine acting at adenosine A1 receptors in the anticonvulsant success of dietary therapy in vitro and in vivo. Our expertise in bioenergetics, adenosine regulation and epilepsy, coupled with unique and complementary methodological approaches, will yield clear experimental outcomes. The long-term goal of this research is to understand critical mechanisms underlying metabolic strategies and yield new options in the treatment of epilepsy and other conditions such as brain injury and stroke, where adenosine offers therapeutic benefits. PUBLIC HEALTH RELEVANCE: Low carbohydrate "ketogenic" diets prevent epileptic seizures and protect neurons, but the reason why dietary therapy is successful is unknown. We hypothesize that ketogenic diets increase adenosine, the brain's own seizure-control molecule. Ultimately, understanding the relationship between adenosine and ketogenic diet therapy will facilitate development of an entirely new family of treatments for epilepsy that are easy to administer, effective and well-tolerated.

描述（由申请人提供）：癫痫症影响所有年龄段人口的大约 1%，是最常见的慢性神经系统疾病之一。不幸的是，目前的药物治疗无法充分控制高达 35% 的癫痫患者的癫痫发作。作为替代方案，高脂肪低碳水化合物（生酮）饮食疗法对医学上难治性癫痫非常有效，其成功的机制可以为了解具有代谢基础的其他神经系统疾病提供见解。尽管人们对此很感兴趣，但临床上确定的生酮饮食疗法抗惊厥成功的关键机制仍然未知。腺苷是 ATP 的核心分子，是一种抑制性神经调节剂，将细胞代谢直接与神经元活动联系起来。了解如何调节腺苷（一种内源性抗惊厥剂和神经保护剂）可以提供强大的治疗益处。类似于生酮饮食在难治性癫痫方面的成功，腺苷在耐药性癫痫模型中是一种有效的抗惊厥药。中心假设是生酮饮食会增加腺苷 A1 受体的激活，而腺苷抑制作用的增加对于生酮饮食疗法的抗惊厥成功至关重要。为了检验这一假设，在对具有正常或基因改变腺苷信号传导的大鼠和小鼠进行生酮饮食治疗后，将应用生物能量、神经化学、电生理学和行为技术。使用最准确的生物能量和神经化学技术的实验将量化能量分子、腺苷、腺苷受体和酮体的变化（目标 1）。将使用详细的电生理学和电化学来量化腺苷对突触传递和神经元兴奋性影响的变化（目标 2）。使用基于遗传的癫痫发作或癫痫模型的行为范式进行的实验将量化癫痫发作频率和严重程度的变化（目标 3）。来自其他人和我们的初步和已发表的数据支持生酮策略增加腺苷水平和作用的假设。拟议的实验将测量腺苷水平，并测试腺苷作用于腺苷 A1 受体在体外和体内饮食疗法抗惊厥成功中的作用。我们在生物能学、腺苷调节和癫痫方面的专业知识，加上独特和互补的方法学方法，将产生明确的实验结果。这项研究的长期目标是了解代谢策略的关键机制，并为治疗癫痫和脑损伤和中风等其他疾病提供新的选择，腺苷在这些疾病中具有治疗作用。公共卫生相关性：低碳水化合物“生酮”饮食可以预防癫痫发作并保护神经元，但饮食疗法成功的原因尚不清楚。我们假设生酮饮食会增加腺苷，即大脑自身的癫痫控制分子。最终，了解腺苷和生酮饮食疗法之间的关系将有助于开发易于管理、有效且耐受性良好的全新癫痫治疗家族。