The Role of Adenosine in Ketogenic Diet Therapy

描述（由申请人提供）：癫痫影响所有年龄组中约1%的人群，是最常见的慢性神经系统疾病之一。不幸的是，目前的药物治疗不能充分控制高达35%的癫痫患者的癫痫发作。作为一种替代方案，高脂肪低碳水化合物（生酮）饮食治疗在医学难治性癫痫中可能非常有效，其成功的机制可以提供对其他具有代谢基础的神经系统疾病的深入了解。尽管有强烈的兴趣，但生酮饮食疗法临床上确定的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质，将细胞代谢与神经元活动直接联系起来。了解如何调节腺苷，内源性抗惊厥和神经保护剂，提供了强大的治疗效益。类似于生酮饮食治疗难治性癫痫的成功，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增加腺苷A1受体活化，并且腺苷的这种增加的抑制作用对于生酮饮食疗法的抗惊厥成功至关重要。为了验证这一假设，将在具有正常或遗传改变的腺苷信号传导的大鼠和小鼠中进行生酮饮食治疗后应用生物能量、神经化学、电生理和行为技术。使用最精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）。腺苷对突触传递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进行量化（目的2）。使用基于遗传的癫痫发作或模型癫痫的行为范例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的水平，并测试腺苷作用于腺苷A1受体在体外和体内饮食疗法的抗惊厥成功中的作用。我们在生物能量学，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，并在癫痫和其他疾病（如脑损伤和中风）的治疗中产生新的选择，其中腺苷提供了治疗益处。 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。我们假设生酮饮食增加了腺苷，大脑自身的代谢控制分子。最终，了解腺苷和生酮饮食疗法之间的关系将有助于开发一个全新的癫痫治疗家族，这些家族易于管理，有效且耐受性良好。

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.