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%的人口，是最普遍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。作为一种替代疗法，高脂肪低碳水化合物（生酮）饮食治疗对难治性癫痫非常有效，其成功背后的机制可以为其他具有代谢基础的神经系统疾病提供见解。尽管有强烈的兴趣，但生酮饮食疗法在临床建立抗惊厥成功的关键机制仍不清楚。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，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了腺苷A1受体的激活，并且这种增加的腺苷抑制影响对于生酮饮食治疗的抗惊厥成功至关重要。为了验证这一假设，生物能量、神经化学、电生理和行为技术将在生酮饮食治疗后应用于正常或基因改变的腺苷信号的大鼠和小鼠。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（目的1）。腺苷对突触传递和神经元兴奋性影响的变化将通过详细的电生理学和电化学来量化（目的2）。使用基于基因的癫痫发作或模拟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（目标3）。来自其他人和我们的初步和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受体在体外和体内抗惊厥饮食治疗成功中的作用。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，并为癫痫和其他疾病（如脑损伤和中风）的治疗提供新的选择，在这些疾病中腺苷提供治疗益处。

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.