Paul Steven M, Pinna Graziano, Guidotti Alessandro
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
Neurobiol Stress. 2020 Mar 14;12:100215. doi: 10.1016/j.ynstr.2020.100215. eCollection 2020 May.
Allopregnanolone is synthesized in the central nervous system either from cholesterol or from steroid hormone precursors like progesterone and pregnenolone. Over the past 30 years, direct and rapid, non-genomic actions of allopregnanolone and its derivatives via GABA receptors have been demonstrated. Changes in brain levels of allopregnanolone during pregnancy and in the postpartum period, or during exposure to protracted stress appear to play a crucial role in the pathophysiology of mood disorders. The discovery that allopregnanolone at low (nanomolar) concentrations elicits marked anxiolytic, anti-stress and antidepressant effects by facilitating allosterically the action of GABA at extrasynaptic GABA receptors has provided new perspectives for the discovery of novel drugs useful for the treatment of mood disorders. These findings have led to the seminal clinical studies that recently demonstrated that treatment with allopregnanolone (i.e., brexanolone) can dramatically and rapidly improve the symptoms of postpartum depression in many patients.
别孕烯醇酮在中枢神经系统中可由胆固醇合成，也可由孕酮和孕烯醇酮等甾体激素前体合成。在过去30年里，已证实别孕烯醇酮及其衍生物通过GABA受体产生直接、快速的非基因组作用。孕期和产后或长期应激期间，大脑中别孕烯醇酮水平的变化似乎在情绪障碍的病理生理学中起关键作用。低（纳摩尔）浓度的别孕烯醇酮通过变构促进GABA在突触外GABA受体上的作用，从而产生显著的抗焦虑、抗应激和抗抑郁作用，这一发现为发现用于治疗情绪障碍的新药提供了新的视角。这些发现促成了开创性的临床研究，最近的研究表明，使用别孕烯醇酮（即布雷沙诺龙）治疗可使许多产后抑郁症患者的症状迅速得到显著改善。
