17α-Estradiol is generated locally in the male rat brain and can regulate GAD65 expression and anxiety

NEUROPHARMACOLOGY

卷:90

Article

Ikeda, Takamitsu¹  Makino, Yukiko²  Yamada, Maki K.^1,3 

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Chem Pharmacol Lab, Bunkyo Ku, Tokyo 1130033, Japan

[2] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Chem & Biol, Bunkyo Ku, Tokyo 1130033, Japan

[3] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan

关键词: Estrogen;    Female hormone;    Inhibition;    Anti-anxiety;    Aromatase;    AKR1C;   

DOI  :  10.1016/j.neuropharm.2014.10.019

来源: Elsevier

【 摘 要 】

Increasing evidence suggests that 17 beta-estradiol, a sex hormone, is synthesized by neurons. In addition, 17 alpha-estradiol, the stereoisomer of 17 beta-estradiol, is reported to be the dominant form in the male mouse brain. However, probably because the method to detect these isomers requires unusual and precise experimental design, the presence of this endogenous 17 alpha-estradiol has not been reported subsequently and the actual role is therefore not well elucidated. We first quantified the estradiol level in hippocampal extracts using gas chromatography/mass spectrometry. As a result, 17 alpha-estradiol was found in all of the male rats tested, while that of 17 beta-estradiol was detected only in a certain subset. The estrogen-biosynthesis inhibitor letrozole decreased the expression of the major presynaptic GABA synthesizing enzyme GAD65 in cultured neurons and the effect was abrogated by exogenously supplied 17 alpha-estradiol. Next, injection of the inhibitor into the brain reduced the 17 alpha-estradiol level, indicating its biogenesis in the brain. Under the same conditions, immuno-staining of GAD65 was also decreased. Furthermore, the inhibitor treatment increased anxiety index of rats in the open field and this was ameliorated by the addition of 17 alpha-estradiol. We showed that 17 alpha-estradiol was generated in the brain and acted as a regulator of inhibitory neurotransmission as well as behavior. These results may have implications for a variety of diseases, such as the menopausal depression and Alzheimer's disease that have been reported to be related to estrogen levels. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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