Potentiation of 17 beta-estradiol synthesis in the brain and elongation of seizure latency through dietary supplementation with docosahexaenoic acid

Several studies have shown that docosahexaenoic acid (DHA) attenuates epileptic seizures; however, the molecular mechanism by which it achieves this effect is still largely unknown. DHA stimulates the retinoid X receptor, which reportedly regulates the expression of cytochrome P450 aromatase (P450arom). This study aimed to clarify how DHA suppresses seizures, focusing on the regulation of 17β-estradiol synthesis in the brain. Dietary supplementation with DHA increased not only the expression of P450arom, but also 17β-estradiol in the cerebral cortex. While DHA did not affect the duration or scores of the seizures induced by pentylenetetrazole, DHA significantly prolonged the seizure latency. A P450arom inhibitor, letrozole, reduced 17β-estradiol levels and completely suppressed the elongation of seizure latency elicited by DHA. These results suggest that DHA delays the onset of seizures by promoting the synthesis of 17β-estradiol in the brain. DHA upregulated the expression of anti-oxidative enzymes in the cerebral cortex. The oxidation in the cerebral cortex induced by pentylenetetrazole was significantly attenuated by DHA, and letrozole completely inhibited this suppressive action. Thus, the anti-oxidative effects of 17β-estradiol may be involved in the prevention of seizures mediated by DHA. This study revealed that 17β-estradiol in the brain mediated the physiological actions of DHA.This work was partially supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan, KAKENHI for Y.I., K.I. and T.Y. (Nos. 26740024, 26460139 and 25340047), a grant from the Mishima Kaiun Memorial Foundation for Y.I. and a grant from the SKYLARK Food Science Institute for Y.I. This work was also financially supported in part by Tokushima Bunri University. We thank Y. Kamihashi, Y. Utagawa, and K. Kojima for their technical assistance. We also acknowledge S. Smiley-Jewell and M. Paz Prada for editing the manuscript. This manuscript has been checked by a professional language editing service, American Journal Experts