Ikeda Takamitsu, Makino Yukiko, Yamada Maki K
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Laboratory of Chemistry and Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Neuropharmacology. 2015 Mar;90:9-14. doi: 10.1016/j.neuropharm.2014.10.019. Epub 2014 Nov 6.
Increasing evidence suggests that 17β-estradiol, a sex hormone, is synthesized by neurons. In addition, 17α-estradiol, the stereoisomer of 17β-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 17α-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, 17α-estradiol was found in all of the male rats tested, while that of 17β-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 17α-estradiol. Next, injection of the inhibitor into the brain reduced the 17α-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 17α-estradiol. We showed that 17α-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.
越来越多的证据表明，性激素17β-雌二醇是由神经元合成的。此外，据报道，17β-雌二醇的立体异构体17α-雌二醇是雄性小鼠大脑中的主要形式。然而，可能是因为检测这些异构体的方法需要特殊且精确的实验设计，这种内源性17α-雌二醇的存在随后未被报道，其实际作用也因此没有得到很好的阐明。我们首先使用气相色谱/质谱法对海马提取物中的雌二醇水平进行了定量。结果发现，在所有测试的雄性大鼠中都检测到了17α-雌二醇，而仅在特定亚组中检测到了17β-雌二醇。雌激素生物合成抑制剂来曲唑降低了培养神经元中主要突触前GABA合成酶GAD65的表达，而外源性提供的17α-雌二醇可消除这种作用。接下来，将抑制剂注射到大脑中可降低17α-雌二醇水平，表明其在大脑中的生物合成。在相同条件下，GAD65的免疫染色也减少了。此外，抑制剂处理增加了大鼠在旷场中的焦虑指数，而添加17α-雌二醇可改善这种情况。我们表明，17α-雌二醇在大脑中生成，并作为抑制性神经传递和行为的调节剂发挥作用。这些结果可能对多种疾病有影响，例如据报道与雌激素水平相关的更年期抑郁症和阿尔茨海默病。
