Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures.
Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures.
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DOI：
10.1371/journal.pone.0080922
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hammock BD
中科院分区：
文献类型：
--
作者：
Inceoglu B;Zolkowska D;Yoo HJ;Wagner KM;Yang J;Hackett E;Hwang SH;Lee KS;Rogawski MA;Morisseau C;Hammock BD
在大脑中，癫痫发作会导致释放大量多不饱和脂肪酸，包括花生四烯酸 (ARA)。 ARA 是环氧合酶、脂氧合酶和细胞色素 P450 酶代谢的三种主要酶促途径的底物。这些酶将 ARA 转化为有效的脂质介质，包括前列腺素、白三烯和环氧二十碳三烯酸 (EET)。前列腺素和白三烯主要是促炎分子，使神经元敏感，而 EET 具有抗炎作用并降低神经元的兴奋性。最近的证据表明 GABA 相关的作用模式可能由神经类固醇介导。在这里，我们使用化学诱发癫痫发作的模型测试了这一假设。通过抑制可溶性环氧化物水解酶（sEH）（将 EET 代谢为无活性分子的主要酶）、通过基因删除 sEH 以及直接将 EET 注射到大脑中，可以调节大脑中 EET 的水平。所有三种方法都延迟了 GABA 拮抗剂引发的癫痫发作，但不能延迟通过其他机制引起的癫痫发作。非那雄胺对神经类固醇合成的抑制部分阻断了 sEH 抑制剂的抗惊厥作用，而非活性剂量的神经类固醇四氢孕酮的功效则因 sEH 抑制而增强。与早期的发现一致，大脑中前列腺素的水平升高。相反，癫痫发作后生物活性 EpFA 的水平下降。总体而言，这些结果表明 EET 是天然分子，可通过调节 GABA 活性来抑制癫痫相关兴奋性的强直成分，并且对 EET 介导的大脑信号传导的探索可能会产生治疗惊厥性疾病的替代方法。
In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders.
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影响因子：
1.7
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