MEASUREMENTS AND METABOLISM OF NEUROSTEROIDS IN THE CENTRAL NERVOUS SYSTEM

中枢神经系统中神经类固醇的测量和代谢

• 批准号: 6097570
• 负责人: Hee-Yong Kim
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6097570
• 关键词: Primates; alcoholism /alcohol abuse; brain metabolism; cerebrospinal fluid; drug withdrawal; electrospray ionization mass spectrometry; ethanol; laboratory rat; neuroendocrine system; pregnanolone; progesterone analog; steroid hormone metabolism

The principal objective of this study is to determine the effect of ethanol on the metabolism of neurosteroids in the central nervous system. Neurosteroids such as 5a-pregnane-3a-ol-20-one (5a,3a-THP or Allopregnanolone) and 5a-pregnane-3a,21-diol-20- one (THDOC) have been shown to modulate the GABA/benzodiazepine binding sites and to exert anxiolytic and hypnotic effects. Modulation of these neurosteroids in the central nervous system by ethanol may be one of the underlying mechanisms for stress- related situations often observed in human alcoholics during withdrawal. In the past year, we have established a mass spectrometric technique which has adequate sensitivity to routinely measure trace levels of neurosteroids in cerebrospinal fluid(CSF). Specifically, GC/MS was used after derivatizing neurosteroids with an electron capturing moiety. Using this approach, we were able to detect pregnenolone, 5a,3a-, 5b,3a-, 5a,3b-THP, androsterone, testosterone, dihydrotestosterone and dihydroepandrosterone from human and monkey CSF samples. We found that human and monkey CSF contain both 5a,3a- and 5a,3b- THP at 5-170 picogram/ml concentrations while 5b,3a-THP is present at a concentration less than 5 pg/mL.

这项研究的主要目的是确定 乙醇对神经类固醇代谢的影响 中枢神经系统。神经类固醇，例如 5A-Pregnane-3A-OL-20-ONE（5A，3A-THP或ALLOPREGNANOLONE）和 5a-pregnane-3a，21-二醇-20-一（thdoc）已显示为 调节GABA/Benzodiazepine结合位点并施加 抗焦虑和催眠作用。这些神经类固醇的调节 在中枢神经系统中，乙醇可能是 经常观察到与压力相关情况的基本机制 在戒断期间的人类酗酒者中。在过去的一年中，我们有 建立了足够的质谱技术 对常规测量神经类固醇的敏感性 脑脊液（CSF）。具体而言，使用GC/MS 用电子捕获部分的电子衍生神经类固醇。使用 这种方法，我们能够检测到妊娠5a，3a-，3a-，5b，3a-， 5A，3B-THP，雄酮，睾丸激素，二氢睾丸激素和 来自人类和猴子CSF样品的二羟烷酮。我们 发现人和猴子CSF均包含5a，3a-和5a，3b- THP在5-170二十字图/ml浓度时，5b，3a-thp为 以小于5 pg/ml的浓度存在。