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Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research P

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Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research P Journal of Neuroendocrinology, 2016, 28, 10.1111/jne.12351 REVIEW ARTICLE © 2015 British Society for Neuroendocrinology Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research P. Porcu*, A. M. Barron†, C. A. Frye‡§, A. A. Walf‡§¶, S.-Y. Yang**, X.-Y. He**, A. L. Morrow††, G. C. Panzica‡‡ and R. C. Melcangi§§ *Neuroscience Institute, National Research Council of Italy (CNR), Cagliari, Italy. †Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa, Inage-ku, Chiba, Japan. ‡IDEA Network of Biomedical Research Excellence and Department of Chemistry and Biochemistry, University of Alaska–Fairbanks, Fairbanks, AK, USA. §Department of Psychology, The University at Albany, Albany, NY, USA. ¶Department of Cognitive Science, Rensselaer Polytechnic Institute, Troy, NY, USA. **Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. ††Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA. ‡‡Department of Neuroscience, University of Turin, and NICO – Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy. §§Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy. Journal of Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter Neuroendocrinology neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antide- pressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABAA receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in sev- eral animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiologi- cal 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 pharma- cokinetics, 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 17b-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 Correspondence to: P. Porcu, also for neuropsychiatric diseases, including alcohol use disorders. Neuroscience Institute, National a a Research Council of Italy (CNR), Key words: neuroactive steroids, 3 ,5 -THP, translocator protein 18 kDa, pregnane xenobiotic Cittadella Universitaria, 09042 receptor, 17b-hydroxysteroid dehydrogenase type 10, P450 side chain cleavage, Alzheimer’s Monserrato, Cagliari, Italy (e-mail: disease, alcoholism [email protected]). doi: 10.1111/jne.12351 They can be synthesised in the brain de novo from cholesterol, in Introduction which case they have been termed neurosteroids (2), or can reach Neuroactive steroids are endogenous neuromodulators that rapidly the brain from peripheral steroidogenic organs, such as adrenals alter neuronal excitability by binding to membrane receptors (1). and gonads, and are locally metabolised (i.e. aromatisation of 2of19 P. Porcu et al. testosterone into oestradiol) (3). The synthesis of neuroactive ster- that possess the necessary enzymatic machinery to convert choles- oids requires the translocation of cholesterol across the mitochon- terol into neuroactive steroids (4). drial membrane, which occurs through a molecular complex formed The most potent neuroactive steroids are the progesterone by the translocator protein 18 kDa (TSPO), the steroidogenic acute metabolite (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allo- regulatory protein (StAR), the voltage-dependent anion channel pregnanolone) and the deoxycorticosterone (DOC) metabolite protein (VDAC) and the adenine nucleotide transporter protein (3a,5a)-3,21-dihydroxypregnan-20-one (3a,5a-THDOC or allote- (ANT). In the mitochondria, cholesterol is converted to pregnenolone trahydrodeoxycorticosterone), which enhance GABAA receptor medi- by the P450 side-chain cleavage enzyme (P450scc); pregnenolone ated neurotransmission and produce inhibitory neurobehavioural diffuses into the cytosol where it is further metabolised into differ- effects (5). The 3a,5a-reduced metabolites of testosterone and ent neuroactive steroids (Fig. 1). Although TSPO, the rate-limiting dehydroepiandrosterone (DHEA), 3a,5a-androstandiol and 3a,5a- step in neuroactive steroid synthesis, is highly expressed in micro- androsterone, respectively, also potentiate GABAA receptors, albeit glia and astrocytes but less abundant in neurones, neurosteroidoge- with less potency (6). Specific binding sites for neuroactive steroids nesis occurs primarily in principal neurones of several brain areas have been identified on the a subunits of the GABAA receptor that COCH COCH 3 + 3 C = O C = O NAD NADH 17β-HSD10 5α-reductase 3β-HSD P450scc Cholesterol 3α-HSD3 3α,5α-THP NADP+ NADPH 5α-DHP Progesterone Pregnenolone O O HO HO H H 21-hydroxylase P450c17 P450c17 COCH OH COCH OH 2 + 2 NAD NADH 17α-hydroxyprogesterone 17α-hydroxypregnenolone 17β-HSD10 5α-reductase DOC O 3α-HSD3 O + NADPH 3α,5α-THDOCNADP 5α-DHDOC 3β-HSD HO O H H Androstenedione Dehydroepiandrosterone O HO OH Aromatase 17β-HSD 17β-HSD Oestrone OH OH HO 3β-HSD NADH 17β-HSD10 3α-HSD Testosterone 3α-androstenediol O + HO OH NAD Aromatase 5α-reductase 5α-reductase 17β-oestradiol OH O HO 5α-dihydrotestosterone Androstanedione OO H H NADH NADH 17β-HSD10 3α-HSD 17β-HSD10 3α-HSD + + NAD OH NAD O 17β-HSD 3α-androstanediol 3α-androsterone HO HO H H Fig. 1. Outline of neurosteroidogenesis. Neuroactive steroids and neurosteroidogenic enzymes that are potential key therapeutic targets are shown in green. The side chain of cholesterol is cleaved by P450 side-chain cleavage enzyme (P450scc) as cholesterol is transported to the inner mitochondrial membrane and thus converted to pregnenolone. Soluble pregnenolone can enter into the endoplasmic reticulum unaided. 17b-Hydroxysteroid dehydrogenase type 10 (17b- HSD10) catalyses the oxidation of neuroactive steroids in mitochondria with NAD+ as the coenzyme. This enzyme most effectively catalyzes the oxidation of (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP) and (3a,5a)-3,21-dihydroxypregnan-20-one (3a,5a-THDOC) such that it is essential for the homeostasis of these neuroactive steroids, which was controlled by a dual enzyme molecular switch, composed of 17b-HSD10 and 3a-hydroxysteroid dehydrogenase type III (AKR1C2) localised in distinct subcellular compartments, mitochondria and endoplasic reticulum, respectively (164,168). The catalytic efficiencies (kcat/Km)of 17b-HSD10 are as high as 427 and 1381 min/mM for the oxidation of 3a,5a-THP and 3a,5a-THDOC, respectively (163,164). 5a-DHP, 5a-dihydroprogesterone; DOC, deoxycorticosterone; 5a-DHDOC, 5a-dihydrodeoxycorticosterone. © 2015 British Society for Neuroendocrinology Journal of Neuroendocrinology, 2016, 28, 10.1111/jne.12351 Novel targets for neuroactive steroid synthesis and action 3of19 allosterically modulate binding to GABA and benzodiazepine recog- axis function (46,47). The neuroactive steroid response to stress is a nition sites (7). At nanomolar concentrations, 3a,5a-THP enhances complex phenomenon that involves adaptations in GABAA receptor affinity of GABA for its receptor, whereas, at micromolar concentra- plasticity and appears to differ across species (23,48). tions, it directly activates the receptor channel. 3a,5a-THP and Neuroactive steroid concentrations also fluctuate across develop- 3a,5a-THDOC modulate both synaptic and extrasynaptic GABAA ment. Brain levels of 3a,5a-THP are elevated in the embryonic rat, receptors, albeit with higher potency at extrasynaptic receptors that decrease around birth, show a transient increase on days 10–14 contain d subunits (5,6). 3a,5a-THP also modulates serotonin type and remain low until puberty (49). The onset of puberty is associ- 3 receptors, neuronal nicotinic acetylcholine receptors and voltage- ated with a rapid elevation in 3a,5a-THP levels and a marked activated calcium channels, although with micromolar potency (8). increase in extrasynaptic a4bd GABAA receptors, the main target of Another site of 3a,5a-THP action, the nuclear pregnane xenobiotic 3a,5a-THP, through which this steroid is considered to increase receptor (PXR) has been recently identified (9). By contrast, the sul- excitability, and thus exert the ‘paradoxical effect’ of increasing phated derivative
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