Mukai Yoshiyuki, Higashi Tatsuya, Nagura Yukiko, Shimada Kazutake
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Biol Pharm Bull. 2008 Sep;31(9):1646-50. doi: 10.1248/bpb.31.1646.
In this study, we examined the influence of finasteride (FIN), a 5alpha-reductase inhibitor, on the brain levels and metabolism of neurosteroids [allopregnanolone (AP), 3alpha-dihydroprogesterone (3alpha-DHP), progesterone (PROG), 20alpha-dihydroprogesterone and 11-deoxycorticosterone (DOC)] in rats exposed to immobilization stress. For this purpose, the sensitive, reproducible and accurate liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) methods that enable the quantification of trace amounts of brain neurosteroids were first developed. The animal study using these methods demonstrated that FIN dose-dependently inhibits the stress-induced elevation of the brain AP, a potent positive modulator of the gamma-aminobutyric acid (GABA) type A receptors, and a 10 mg/kg dose of FIN can almost completely deplete AP in the brains. The study also found that the 20alpha-reduction of PROG is enhanced when its 5alpha-reduction pathway is inhibited in the brains. No change was found in the brain levels of 3alpha-DHP, another GABAergic neurosteroid, and DOC by the administration of FIN.
在本研究中，我们检测了5α-还原酶抑制剂非那雄胺（FIN）对遭受固定应激的大鼠脑内神经甾体[别孕烯醇酮（AP）、3α-二氢孕酮（3α-DHP）、孕酮（PROG）、20α-二氢孕酮和11-脱氧皮质酮（DOC）]水平及代谢的影响。为此，首先开发了灵敏、可重复且准确的液相色谱-电喷雾电离-串联质谱（LC-ESI-MS/MS）方法，用于定量痕量脑内神经甾体。使用这些方法进行的动物研究表明，FIN剂量依赖性地抑制应激诱导的脑内AP升高，AP是γ-氨基丁酸（GABA）A型受体的强效正性调节剂，10 mg/kg剂量的FIN几乎可完全耗尽脑内的AP。该研究还发现，当脑内PROG的5α-还原途径受到抑制时，其20α-还原作用增强。给予FIN后，另一种GABA能神经甾体3α-DHP和DOC的脑内水平未发现变化。
