Neuroscience Program and Psychology Department, Trinity College, Hartford, CT 06106, USA.
Epilepsy Res. 2012 Jul;100(3):229-38. doi: 10.1016/j.eplepsyres.2011.07.014. Epub 2011 Aug 30.
ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A(1) receptor (A(1)R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A(1)Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A(1)R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A(1)Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms.
三磷酸腺苷（ATP）和腺苷是嘌呤类物质，在细胞代谢和神经元信号中发挥双重作用。作为 A1 受体（A1R）亚型的配体，腺苷直接作用于神经元以抑制兴奋性，是一种强大的内源性神经保护和抗惊厥分子。先前的研究表明，当动物接受生酮饮食（一种已建立的代谢治疗方法，可减少癫痫发作）时，ATP 和其他细胞能量参数会增加，但嘌呤、神经元兴奋性和生酮饮食之间的关系尚不清楚。最近的体内和体外研究检验了一个具体的假设，即 A1R 上的腺苷作用是生酮饮食治疗成功的关键机制，并且直接证明了 A1R 与生酮饮食的抗癫痫作用有关。具体来说，生酮饮食的体外模拟揭示了 A1R 依赖性代谢自分泌超极化作用于海马神经元。同时，将生酮饮食应用于具有自发电描记发作的转基因小鼠模型体内，揭示了完整的 A1R 对于饮食的抗惊厥作用是必需的。这是第一个将 A1R 与生酮饮食的抗癫痫作用直接联系起来的体内证据。还讨论了嘌呤与生酮饮食之间关系的其他预测。总之，嘌呤作用的最新研究可能为代谢治疗提供新的机会，并深入了解其潜在机制。
