The Role of Adenosine in Ketogenic Diet Therapy

腺苷在生酮饮食疗法中的作用

• 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
• 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

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）：癫痫会影响所有年龄段的大约1％的人口，并且是最普遍的慢性神经系统疾病之一。不幸的是，当前的药理学治疗不能在高达35％的癫痫患者中充分控制癫痫发作。作为替代方法，具有高脂低碳水化合物（生酮）饮食的治疗可以在医学上消除癫痫病中非常有效，并且其成功的基础机制可以提供对其他具有代谢底层抑制的神经系统疾病的见识。尽管感兴趣，但生酮饮食疗法的临床确立的抗惊厥成功的基础的关键机制仍然未知。 ATP的核心分子腺苷是一种抑制性神经调节剂，将细胞代谢直接与神经元活性联系起来。了解如何调节内源性抗惊厥药和神经保护剂腺苷具有强大的治疗益处。类似于生酮饮食在难治性癫痫中的成功，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，并且这种增加的腺苷抑制作用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，将在酮饮食治疗后，将应用生物能，神经化学，电生理学和行为技术，并在具有正常或遗传性的腺苷信号传导的大鼠和小鼠中使用。使用最准确的生物能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（AIM 1）。腺苷对突触传播和神经元兴奋性的影响的变化将使用详细的电生理学和电化学来量化（AIM 2）。使用基于遗传的癫痫发作或建模癫痫的行为范式的实验将量化癫痫发作频率和严重程度的变化（AIM 3）。 来自他人的初步和发布的数据，美国支持了生酮策略增加腺苷的水平和作用的假设。提出的实验将测量腺苷的水平，并测试腺苷作用在腺苷A1受体中的作用，在体外和体内饮食治疗的抗惊厥成功中。我们在生物能，腺苷调节和癫痫的专业知识，再加上独特的和互补的方法论方法，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基本关键机制，并在治疗癫痫病和其他疾病（例如脑损伤和中风）方面产生新的选择，腺苷带来治疗益处。 公共卫生相关性：低碳水化合物的“生酮”饮食可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大脑自身癫痫发作控制的腺苷。最终，了解腺苷与生酮饮食疗法之间的关系将有助于开发全新的癫痫疗法家族，这些疗法易于给药，有效且耐受性良好。