RRC ID 63781
Author Oguro A, Ishihara Y, Siswanto FM, Yamazaki T, Ishida A, Imaishi H, Imaoka S.
Title 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.
Journal Biochim Biophys Acta Mol Cell Biol Lipids
Abstract 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.
Volume 1866(2)
Pages 158858
Published 2021-2-1
DOI 10.1016/j.bbalip.2020.158858
PII S1388-1981(20)30250-X
PMID 33279658
MeSH Animals Brain / drug effects Brain / metabolism Brain / pathology Catalase / metabolism Cytochrome P-450 Enzyme System / metabolism Disease Models, Animal Docosahexaenoic Acids / administration & dosage* Docosahexaenoic Acids / metabolism Epoxide Hydrolases / antagonists & inhibitors Epoxide Hydrolases / metabolism Fatty Acids, Unsaturated / metabolism* Humans Male NF-E2-Related Factor 2 / metabolism Neuroprotective Agents / administration & dosage* Neuroprotective Agents / metabolism Oxidation-Reduction / drug effects Parkinson Disease, Secondary / chemically induced Parkinson Disease, Secondary / drug therapy* Parkinson Disease, Secondary / pathology Rats Rotenone / toxicity Superoxide Dismutase-1 / metabolism
IF 4.519
Human and Animal Cells PC-12(RCB0009)