Seizure Control by Derivatives of Medium Chain Fatty Acids Associated with the Ketogenic Diet Show Novel Branching-Point Structure for Enhanced Potency
Seizure Control by Derivatives of Medium Chain Fatty Acids Associated with the Ketogenic Diet Show Novel Branching-Point Structure for Enhanced Potency
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DOI：
10.1124/jpet.114.218768
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Williams, Robin S. B.
中科院分区：
文献类型：
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作者：
Chang, Pishan;Zuckermann, Alexandra M. E.;Williams, Robin S. B.
中链甘油三酯（MCT）生酮饮食是耐药性癫痫的主要治疗方法，但由于耐受性差，特别是在成人中存在问题。辛酸（OA）的支链衍生物，在饮食中提供的中链脂肪已被建议作为潜在的新的治疗耐药性癫痫，但这种功能的结构基础尚未确定。在这里，我们研究了支链中链脂肪酸的结构变体作为新的脂肪控制治疗方法。我们首先采用了一系列甲基分支OA衍生物，并使用GABA（A）受体拮抗剂戊四氮诱导大鼠海马切片中的癫痫样活性，我们显示出较强的分支点特异性活性，改善了相关的癫痫治疗丙戊酸。使用低镁条件下诱导谷氨酸兴奋性毒性大鼠原代海马神经元培养的神经保护的评估，我们也显示了结构依赖性相同的癫痫发作控制，这表明这些化合物在癫痫发作控制和神经保护的相关机制的行动。相反，这些化合物对组蛋白脱乙酰酶（HDAC）抑制的作用（与致畸性相关）显示与治疗功效无关。此外，起始化合物的小的结构修饰提供了没有HDAC抑制作用的活性化合物。最后，使用多种体内癫痫发作模型，我们确定了治疗癫痫的有效先导候选药物。因此，本研究确定了一个与MCT生酮饮食相关的新型脂肪酸家族，有望成为癫痫控制和可能的其他MCT生酮饮食反应性疾病（如阿尔茨海默病）的新治疗方法。
The medium chain triglyceride (MCT) ketogenic diet is a major treatment of drug-resistant epilepsy but is problematic, particularly in adults, because of poor tolerability. Branched derivatives of octanoic acid (OA), a medium chain fat provided in the diet have been suggested as potential new treatments for drug-resistant epilepsy, but the structural basis of this functionality has not been determined. Here we investigate structural variants of branched medium chain fatty acids as new seizure-control treatments. We initially employ a series of methyl-branched OA derivatives, and using the GABA(A) receptor antagonist pentylenetetrazol to induce seizure-like activity in rat hippocampal slices, we show a strong, branch-point-specific activity that improves upon the related epilepsy treatment valproic acid. Using low magnesium conditions to induce glutamate excitotoxicity in rat primary hippocampal neuronal cultures for the assessment of neuroprotection, we also show a structural dependence identical to that for seizure control, suggesting a related mechanism of action for these compounds in both seizure control and neuroprotection. In contrast, the effect of these compounds on histone deacetylase (HDAC) inhibition, associated with teratogenicity, shows no correlation with therapeutic efficacy. Furthermore, small structural modifications of the starting compounds provide active compounds without HDAC inhibitory effects. Finally, using multiple in vivo seizure models, we identify potent lead candidates for the treatment of epilepsy. This study therefore identifies a novel family of fatty acids, related to the MCT ketogenic diet, that show promise as new treatments for epilepsy control and possibly other MCT ketogenic diet-responding conditions, such as Alzheimer disease.