Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone.
Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone.
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DOI：
10.1177/2470547018818555
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Rasmusson, Ann M
中科院分区：
文献类型：
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作者：
Liang, Jennifer J;Rasmusson, Ann M
异孕酮和孕酮是一种由大脑、肾上腺、卵巢和睾丸中的孕酮合成的神经类固醇，与一系列神经精神疾病有关，包括癫痫、创伤后应激障碍、重度抑郁症、产后抑郁症、经前焦虑症、慢性疼痛、帕金森病、阿尔茨海默病、神经创伤和中风。异孕酮和孕酮均能促进γ -氨基丁酸（GABA）对GABAA受体的作用，并在硫酸酸化后拮抗n -甲基- d -天冬氨酸受体。它们在神经生理稳态和应激适应中发挥着无数的作用，同时发挥着抗焦虑、抗抑郁、抗伤害、抗惊厥、抗炎、促进睡眠、稳定记忆、神经保护、促髓鞘形成和神经原性作用。鉴于这些神经类固醇是根据需要重新合成的，本文详细介绍了在类固醇细胞中将胆固醇生化转化为异孕酮和孕酮的分子步骤。虽然对神经甾体形成的早期步骤了解很多，但对异孕酮酮和孕酮特异性合成的转录、翻译和翻译后过程知之甚少。需要进一步的研究来阐明这些机制，以及优化干预的时间和剂量，以改变这些神经类固醇的合成或水平。这应该包括针对许多神经精神疾病的新疗法的开发，这些疾病是由这些神经类固醇失调造成的。
Allopregnanolone and pregnanolone-neurosteroids synthesized from progesterone in the brain, adrenal gland, ovary and testis-have been implicated in a range of neuropsychiatric conditions including seizure disorders, post-traumatic stress disorder, major depression, post-partum depression, pre-menstrual dysphoric disorder, chronic pain, Parkinson's disease, Alzheimer's disease, neurotrauma, and stroke. Allopregnanolone and pregnanolone equipotently facilitate the effects of gamma-amino-butyric acid (GABA) at GABAA receptors, and when sulfated, antagonize N-methyl-D-aspartate receptors. They play myriad roles in neurophysiological homeostasis and adaptation to stress while exerting anxiolytic, antidepressant, anti-nociceptive, anticonvulsant, anti-inflammatory, sleep promoting, memory stabilizing, neuroprotective, pro-myelinating, and neurogenic effects. Given that these neurosteroids are synthesized de novo on demand, this review details the molecular steps involved in the biochemical conversion of cholesterol to allopregnanolone and pregnanolone within steroidogenic cells. Although much is known about the early steps in neurosteroidogenesis, less is known about transcriptional, translational, and post-translational processes in allopregnanolone- and pregnanolone-specific synthesis. Further research to elucidate these mechanisms as well as to optimize the timing and dose of interventions aimed at altering the synthesis or levels of these neurosteroids is much needed. This should include the development of novel therapeutics for the many neuropsychiatric conditions to which dysregulation of these neurosteroids contributes.