Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre 90050-170, RS, Brazil.
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor Str., Chicago, IL 60612, USA.
Int J Mol Sci. 2021 May 23;22(11):5495. doi: 10.3390/ijms22115495.
Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.
在应激条件下，下丘脑-垂体-肾上腺（HPA）轴作用于促进短暂的生理适应，而这些适应通常在应激刺激不再存在后得到解决。除了皮质醇等糖皮质激素外，神经甾体孕烷醇酮（3α,5α-四氢孕酮，3α-羟基-5α-孕烷-20-酮）也参与恢复体内平衡的负反馈机制。慢性、反复暴露于应激会损害 HPA 轴的反应性并降低孕烷醇酮水平，从而参与精神障碍（如重度抑郁症（MDD）和创伤后应激障碍（PTSD））的发病机制。MDD 和 PTSD 患者的 HPA 轴调节存在异常，例如皮质醇水平改变或地塞米松抑制试验中皮质醇释放不能被抑制。在此，我们综述了孕烷醇酮作为一种强效的、阳性的 GABA 能神经调质的神经生理学作用，以及其抑制 HPA 轴的能力。讨论了孕烷醇酮在应激诱导的病理生理学机制（包括 MDD 和 PTSD）中的作用，及其作为这些疾病的治疗靶点和生物标志物的潜在作用。
