||Neurosteroidogenesis today: Novel targets for neuroactive steroid synthesis and action and their relevance for translational research.
Porcu, Patrizia ,
Barron, Anna ,
Anne Frye, Cheryl ,
A Walf, Alicia ,
Song-Yu, Yang ,
Xue-Ying, He ,
Leslie Morrow, A ,
Carlo Panzica, GianC Melcangi, Roberto
Journal of neuroendocrinology
, p.12351 , 2015-12 , Wiley & Sons
Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-amino-butyric type A (GABAA ) receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions such as stress response, puberty, ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurologic diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability that limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarizes recent approaches that target the neuroactive steroid biosynthetic pathway at different levels in order to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa (TSPO), and the pregnane xenobiotic receptor (PXR), as well as targeting of specific neurosteroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) or P450 side chain cleavage (P450scc). Enhanced neurosteroidogenesis through these targets may be beneficial for neurodegenerative diseases such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders. This article is protected by copyright. All rights reserved.