Contribution of DHA diols (19,20-DHDP) produced by cytochrome P450s and soluble epoxide hydrolase to the beneficial effects of DHA supplementation in the brains of rotenone-induced rat models of Parkinson's disease
Contribution of DHA diols (19,20-DHDP) produced by cytochrome P450s and soluble epoxide hydrolase to the beneficial effects of DHA supplementation in the brains of rotenone-induced rat models of Parkinson's disease
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DOI：
10.1016/j.bbalip.2020.158858
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发表时间：
2021-02-01
影响因子：
4.8
通讯作者：
Imaoka, Susumu
中科院分区：
文献类型：
--
作者：
Oguro, Ami;Ishihara, Yasuhiro;Imaoka, Susumu
二十二碳六烯酸（DHA）已被证明对帕金森病具有神经保护作用，但其潜在机制尚未完全阐明。DHA通过细胞色素P450（P450 s）代谢为DHA环氧化物（EDP）和氢氧化物，并且EDP通过可溶性环氧化物水解酶（sEH）进一步羟基化为相应的二醇，0-二羟基二十二碳五烯酸（DHDP）。在本研究中，我们研究了这些DHA代谢物在补充DHA对鱼藤酮诱导的帕金森病大鼠模型的有益作用中的作用。LC-MS代谢产物分析表明，CYP 2A 1、2C 11、2C 13、2C 23和2 E1参与了EDP的形成，这些P450和sEH在大鼠脑中表达。我们发现，DHA补充剂在大鼠中改善鱼藤酮诱导的运动功能障碍。此外，DHA逆转了纹状体中酪氨酸羟化酶的减少和鱼藤酮产生的脂质过氧化作用的增加。补充DHA还诱导抗氧化基因的mRNA表达，如sod 1和过氧化氢酶，以及纹状体中Nrf 2蛋白的表达。然而，补充DHA的这些作用被与sEH抑制剂TPPU共同补充所消除。补充DHA增加了大鼠脑中19，20-DHDP的量，而EDP的量没有显着增加。此外，TPPU抑制了脑中DHDP的增加和EDPs的增加。在PC 12细胞中，19，20-DHDP沿着Nrf 2诱导增加sod 1和过氧化氢酶的mRNA水平。这项研究表明，DHA的代谢产物--由P450和sEH产生的DHDP--在改善鱼藤酮诱导的帕金森病中具有重要作用。
Docosahexaenoic acid (DHA) has been shown to have neuroprotective effects in Parkinson's disease, but the underlying mechanism has not been fully elucidated. DHA is metabolized to DHA epoxides (EDPs) and hydroxides by cytochrome P450s (P450s), and EDPs are further hydroxylated to the corresponding diols, 0dihydroxydocosapentaenoic acids (DHDPs) by soluble epoxide hydrolase (sEH). In the present study, we investigated the roles of these DHA metabolites in the beneficial effects of DHA supplementation on a rotenone-induced rat model of Parkinson's disease. Metabolite analysis by LC-MS revealed that CYP2A1, 2C11, 2C13, 2C23, and 2E1 contributed to the formation of EDPs, and these P450s and sEH were expressed in the rat brain. We found that DHA supplementation in rats improved the motor dysfunction induced by rotenone. In addition, DHA reversed the decrease in tyrosine hydroxylase and the increase in lipid peroxidation generated by rotenone in the striatum. DHA supplementation also induced mRNA expression of antioxidant genes, such as sod1 and catalase, and Nrf2 protein expression in the striatum. However, these effects of DHA supplementation were eliminated by cosupplementation with the sEH inhibitor TPPU. Supplementation with DHA increased the amount of 19,20-DHDP in the rat brain, while the amount of EDPs was not significantly increased. In addition, TPPU suppressed the increase in DHDPs and increased EDPs in the brain. In PC12 cells, 19,20-DHDP increased the mRNA levels of sod1 and catalase along with Nrf2 induction. This study suggests that DHA metabolites-DHDPs generated by P450s and sEH-have an important role in improving rotenone-induced Parkinson's disease.