Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan.
Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Feb;1866(2):158858. doi: 10.1016/j.bbalip.2020.158858. Epub 2020 Dec 3.
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, dihydroxydocosapentaenoic 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.
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，但其中的作用机制尚未完全阐明。DHA 可被细胞色素 P450（P450）代谢为 DHA 环氧化物（EDPs）和羟化物，EDPs 进一步被可溶性环氧化物水解酶（sEH）羟基化为相应的二醇，二羟基二十二碳五烯酸（DHDPs）。在本研究中，我们研究了这些 DHA 代谢物在 DHA 补充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 CYP2A1、2C11、2C13、2C23 和 2E1 有助于 EDPs 的形成，这些 P450 和 sEH 在大鼠脑中表达。我们发现，大鼠补充 DHA 可改善鱼藤酮引起的运动功能障碍。此外，DHA 逆转了鱼藤酮引起的纹状体酪氨酸羟化酶减少和脂质过氧化增加。DHA 补充还诱导了抗氧化基因如 sod1 和过氧化氢酶以及 Nrf2 蛋白在纹状体中的 mRNA 表达。然而，这些 DHA 补充的作用被 sEH 抑制剂 TPPU 的共同补充所消除。DHA 补充增加了大鼠脑中 19,20-DHDP 的含量，而 EDPs 的含量没有明显增加。此外，TPPU 抑制了 DHDPs 的增加，并增加了大脑中的 EDPs。在 PC12 细胞中，19,20-DHDP 增加了 sod1 和过氧化氢酶的 mRNA 水平，并诱导了 Nrf2 的表达。本研究表明，P450 和 sEH 生成的 DHA 代谢物-DHDPs 在改善鱼藤酮诱导的帕金森病方面发挥着重要作用。
