title: 17α-estradiol is generated locally in the male rat brain and can regulate GAD65 expression and anxiety.
abstract: 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.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Laboratory of Chemistry and Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Makino
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; PRESTO, The Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan. Electronic address: makiky-tky@umin.ac.jp.
authors.forename: Maki K
authors.initials: MK
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D007150:Immunohistochemistry; D000077289:Letrozole; D008297:Male; D008856:Microscopy, Fluorescence; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology
chemical_list: D002491:Central Nervous System Agents; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: AKR1C; Anti-anxiety; Aromatase; Estrogen; Female hormone; Inhibition