Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research |
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| Authors: | P. Porcu A. M. Barron C. A. Frye A. A. Walf S.‐Y. Yang X.‐Y. He A. L. Morrow G. C. Panzica R. C. Melcangi |
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| Affiliation: | 1. Neuroscience Institute, National Research Council of Italy (CNR), Cagliari, Italy;2. Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa, Inage‐ku, Chiba, Japan;3. IDEA Network of Biomedical Research Excellence and Department of Chemistry and Biochemistry, University of Alaska–Fairbanks, Fairbanks, AK, USA;4. Department of Psychology, The University at Albany, Albany, NY, USA;5. Department of Cognitive Science, Rensselaer Polytechnic Institute, Troy, NY, USA;6. Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA;7. Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA;8. Department of Neuroscience, University of Turin, and NICO 9. – 10. Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy;11. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy |
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| Abstract: | 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 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 the stress response, puberty, the ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurological 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, which limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarises recent approaches that target the neuroactive steroid biosynthetic pathway at different levels aiming to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa and the pregnane xenobiotic receptor, as well as targeting of specific neurosteroidogenic enzymes such as 17β‐hydroxysteroid dehydrogenase type 10 or P450 side chain cleavage. Enhanced neurosteroidogenesis through these targets may be beneficial not only for neurodegenerative diseases, such as Alzheimer's disease and age‐related dementia, but also for neuropsychiatric diseases, including alcohol use disorders. |
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| Keywords: | neuroactive steroids 3α ,5α ‐THP translocator protein 18 kDa pregnane xenobiotic receptor 17β ‐hydroxysteroid dehydrogenase type 10 P450 side chain cleavage Alzheimer's disease alcoholism |
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