Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato CA, Italy; Tourette Syndrome Center, University of Cagliari, Monserrato CA, Italy; Sleep Medicine Center, University of Cagliari, Monserrato CA, Italy; National Institute of Neuroscience (INN), University of Cagliari, Monserrato CA, Italy.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
Neuropharmacology. 2019 Mar 15;147:55-65. doi: 10.1016/j.neuropharm.2018.05.013. Epub 2018 May 11.
Steroids exert a profound influence on behavioral reactivity, by modulating the functions of most neurotransmitters and shaping the impact of stress and sex-related variables on neural processes. This background - as well as the observation that most neuroactive steroids (including sex hormones, glucocorticoids and neurosteroids) are synthetized and metabolized by overlapping enzymatic machineries - points to steroidogenic pathways as a powerful source of targets for neuropsychiatric disorders. Inhibitors of steroidogenic enzymes have been developed and approved for a broad range of genitourinary and endocrine dysfunctions, opening to new opportunities to repurpose these drugs for the treatment of mental problems. In line with this idea, preliminary clinical and preclinical results from our group have shown that inhibitors of key steroidogenic enzymes, such as 5α-reductase and 17,20 desmolase-lyase, may have therapeutic efficacy in specific behavioral disorders associated with dopaminergic hyperfunction. While the lack of specificity of these effects raises potential concerns about endocrine adverse events, these initial findings suggest that steroidogenesis modulators with greater brain specificity may hold significant potential for the development of alternative therapies for psychiatric problems. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.
类固醇通过调节大多数神经递质的功能以及塑造应激和与性别相关的变量对神经过程的影响，对行为反应产生深远影响。这种背景——以及大多数神经活性类固醇（包括性激素、糖皮质激素和神经甾体）是由重叠的酶机制合成和代谢的这一观察结果——表明类固醇生成途径是神经精神疾病的一个强大的靶点来源。类固醇生成酶的抑制剂已被开发并批准用于广泛的泌尿生殖和内分泌功能障碍，为重新利用这些药物治疗精神问题开辟了新的机会。与这一想法一致，我们小组的初步临床和临床前研究结果表明，关键类固醇生成酶（如 5α-还原酶和 17,20 去甲酶-裂合酶）的抑制剂可能对与多巴胺功能亢进相关的特定行为障碍具有治疗效果。虽然这些作用缺乏特异性引起了对内分泌不良事件的潜在担忧，但这些初步发现表明，具有更高大脑特异性的类固醇生成调节剂可能为开发治疗精神问题的替代疗法提供巨大潜力。本文是特刊“药物再利用：旧分子，快速追踪 CNS 疾病药物发现和开发的新途径”的一部分。
