Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.
Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.
复制标题
DOI：
10.1016/j.neuropharm.2015.08.007
复制
发表时间：
2015-12
影响因子：
4.7
通讯作者：
Boison D
中科院分区：
文献类型：
--
作者：
Lusardi TA;Akula KK;Coffman SQ;Ruskin DN;Masino SA;Boison D
癫痫是一种非常普遍的癫痫疾病，其严重程度往往会恶化并且难以治疗。然而，没有任何疗法被证明可以阻止疾病进展或预防癫痫的发展。由于高脂肪低碳水化合物生酮饮食（KD）会增强大脑中的腺苷信号传导，并且腺苷不仅可以抑制癫痫发作，还可以影响癫痫发生，因此我们假设生酮饮食可能通过类似的机制来预防癫痫发生。在这里，我们在两个独立的癫痫发生啮齿动物模型中测试了这一假设。在小鼠中使用戊四唑点燃范例，我们首先表明 KD，而不是传统的抗癫痫药物（丙戊酸），抑制了点燃-癫痫发生。重要的是，在治疗逆转后，在生酮饮食存在下点燃的动物中癫痫阈值保持增加，但在丙戊酸存在下点燃的动物中则没有。接下来，我们测试了生酮饮食是否可以在临床相关的进行性癫痫模型中阻止疾病进展。在毛果芸香碱诱导的癫痫持续状态后出现自发性复发性癫痫发作的癫痫大鼠接受 KD 或对照饮食 (CD) 治疗。 CD 喂养的动物癫痫发作的严重程度和频率都有所进展，而 KD 喂养的动物则表现出癫痫发作的长期减少，并且在饮食逆转后仍持续存在。 KD 治疗与腺苷增加和 DNA 甲基化减少有关，后者在停止饮食后仍得以维持。我们的研究结果表明，生酮饮食可以阻止两种机制不同的癫痫模型的疾病进展，并表明治疗效果背后存在表观遗传机制。
Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects.