Adenosine receptor mediated therapies for SUDEP

项目摘要/摘要 癫痫猝死(SUDEP)仍然是癫痫患者和他们的主要关注对象 家人。据估计，SUDEP的发病率为每1000人年1至2.5人，但潜在的 人们对其中的原因知之甚少。在这里，我们将讨论SUDEP的腺苷假说。癫痫发作 触发腺苷(ADO)的激增，腺苷是终止癫痫所需的内源性药物，但 还通过激活不同亚型的腺苷受体来控制脑干的呼吸功能 (ARS)。我们的主要假设是癫痫诱发的ADO增加与不足相结合 ADO在脑干中的代谢清除可导致AR的致命过度激活，从而导致脑干 调节失调和呼吸功能障碍是SUDEP的沉淀物。为了支持我们的假设，我们 证明一种非选择性AR拮抗剂(咖啡因)减少了啮齿动物模型中的致死性呼吸暂停 癫痫和创伤性脑损伤。我们的初步数据支持ADO与 代谢、AR激活和致命性呼吸暂停。出于这些原因，我们将我们的建议集中在脑干上- SUDEP的依赖呼吸机制。 具体地说，我们将解决我们的核心假设，即对SUDEP的易感性与 脑干呼吸区ADO代谢和信号异常，可通过 增强ADO代谢清除或阻断AR激活的治疗干预。脑干 特定的操作将使我们能够测试ADO在脑干中的特定作用。与癫痫相关的解剖 从呼吸控制功能看ADO代谢和信号在边缘系统中的作用 脑干将为ADO操作预防SUDEP提供一条翻译路径。我们的模特 由于杂合子干扰，系统是一只易患SUDEP的小鼠，ADO的代谢清除受损 腺苷激酶(ADK)基因。在星形胶质细胞中表达的ADK是主要的代谢清除途径 大脑中的ADO。我们的研究目标将在三个具体目标上实现：(1)检验假设SUDEP是 与ADO代谢的不适应变化有关。(2)咖啡因起关键作用的检验假设 在SUDEP易感性方面。(3)检测抑制A2AR激活能否预防SUDEP。预期中的 这项研究的结果表明，癫痫诱导的代谢清除能力 ADO通过脑干决定对SUDEP的易感性。机械研究将确定AR 涉及的子类型。此外，这项研究将有助于澄清长期使用咖啡因是否有益 或者是癫痫患者的危险因素。最后，我们将测试A2AR拮抗剂，它们是 已经在临床开发用于治疗帕金森氏症的药物，可以预防SUDEP。

Project Summary/Abstract Sudden unexpected death in epilepsy (SUDEP) remains a major concern for persons with epilepsy and their families. The incidence of SUDEP is estimated at 1 to 2.5 per 1000 patient years however the underlying reasons are poorly understood. Here we will address the adenosine hypothesis of SUDEP. Epileptic seizures trigger a surge of adenosine (ADO), which is an endogenous agent required for seizure termination, but which also controls respiratory functions in the brainstem by activation of different subtypes of adenosine receptors (ARs). Our overarching hypothesis is that a seizure-induced increase in ADO in combination with insufficient metabolic clearance of ADO in the brainstem can cause fatal over-activation of ARs leading to brainstem dysregulation and respiratory dysfunction as a precipitator of SUDEP. In support of our hypothesis, we demonstrated that a non-selective AR antagonist (caffeine) reduced lethal apnea in rodent models of epilepsy and traumatic brain injury. Our preliminary data support a strong association between ADO metabolism, AR activation, and lethal apnea. For those reasons we focus our proposal on the brainstem- dependent respiratory mechanisms of SUDEP. Specifically, we will address our central hypothesis that the susceptibility to SUDEP is related to abnormal ADO metabolism and signaling in respiratory regions of the brainstem and preventable by therapeutic interventions that enhance metabolic clearance of ADO or block AR activation. Brainstem specific manipulations will allow us to test a specific role of ADO in the brainstem. Dissection of seizure-related functions of ADO metabolism and signaling in the limbic system from respiratory control functions in the brainstem will enable a translational path for ADO-manipulation for the prevention of SUDEP. Our model system is a `SUDEP-prone mouse' with impaired metabolic clearance of ADO due to a heterozygous disruption of the adenosine kinase (Adk) gene. ADK, expressed in astrocytes is the main metabolic clearance route for ADO in the brain. Our research goals will be approached in 3 Specific Aims: (1) Test hypothesis that SUDEP is associated with maladaptive changes in ADO metabolism. (2) Test hypothesis that caffeine plays a critical role in SUDEP susceptibility. (3) Test whether suppression of A2AR activation can prevent SUDEP. The expected outcome of this research is the demonstration that the capacity for the metabolic clearance of seizure-induced ADO through the brainstem determines susceptibility to SUDEP. Mechanistic studies will identify the AR subtypes involved. In addition, this research will help to clarify whether the chronic use of caffeine is of benefit or presents a risk factor for persons with epilepsy. Finally, we will test whether A2AR antagonists, which are already in clinical development for the treatment of Parkinson's disease, can prevent SUDEP.