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通讯作者：
S. Masino;Tianfu Li;P. Theofilas;U. Sandau;D. N. Ruskin;B. Fredholm;J. Geiger;E. Aronica;D. Boison
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作者：
S. Masino;Tianfu Li;P. Theofilas;U. Sandau;D. N. Ruskin;B. Fredholm;J. Geiger;E. Aronica;D. Boison
生酮饮食（KD）是一种高脂肪、低碳水化合物的代谢方案；它在治疗难治性癫痫方面的有效性表明，其抗惊厥作用的机制不同于传统抗癫痫药物的作用机制。最近，生酮饮食和类似的代谢策略在其他神经系统疾病中显示出治疗前景，例如减少脑损伤、疼痛和炎症。在这里，我们发现生酮饮食可以通过增加腺苷 A 1 受体 (A 1 Rs) 的激活来减少小鼠癫痫发作。当给因腺苷代谢或信号传导缺陷引起自发性癫痫发作的转基因小鼠喂食 KD 时，如果小鼠具有完整的 A 1 Rs，癫痫发作几乎消失；如果小鼠表达减少的 A 1 Rs，则癫痫发作减少；如果小鼠缺乏 A 1 Rs，则癫痫发作没有改变。通过注射葡萄糖（代谢逆转）或 A 1 R 拮抗剂（药理学逆转）可恢复癫痫发作。蛋白质印迹分析表明，KD 减少了腺苷激酶（主要的腺苷代谢酶）。重要的是，从难治性癫痫患者身上切除的海马组织显示腺苷激酶增加。因此，我们得出结论，腺苷缺乏可能与人类癫痫有关，并且 KD 可以通过增加 A 1 R 介导的抑制来减少癫痫发作。
A ketogenic diet (KD) is a high-fat, low-carbohydrate metabolic regimen; its effectiveness in the treatment of refractory epilepsy suggests that the mechanisms underlying its anticonvulsive effects differ from those targeted by conventional antiepileptic drugs. Recently, KD and analogous metabolic strategies have shown therapeutic promise in other neurologic disorders, such as reducing brain injury, pain, and inflammation. Here, we have shown that KD can reduce seizures in mice by increasing activation of adenosine A 1 receptors (A 1 Rs). When transgenic mice with spontaneous seizures caused by deficiency in adenosine metabolism or signaling were fed KD, seizures were nearly abolished if mice had intact A 1 Rs, were reduced if mice expressed reduced A 1 Rs, and were unaltered if mice lacked A 1 Rs. Seizures were restored by injecting either glucose (meta-bolic reversal) or an A 1 R antagonist (pharmacologic reversal). Western blot analysis demonstrated that the KD reduced adenosine kinase, the major adenosine-metabolizing enzyme. Importantly, hippocampal tissue resected from patients with medically intractable epilepsy demonstrated increased adenosine kinase. We therefore conclude that adenosine deficiency may be relevant to human epilepsy and that KD can reduce seizures by increasing A 1 R-mediated inhibition.