ReviewNeurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides
Introduction
It is firmly established that steroid hormones play a crucial role in the development and functioning of the central nervous system (CNS) [60], [140], [218], [239], [240], [332], [338], [442], [467], [468], [469], [470], [593], [654], [656], [743], [825]. Depending on their chemical structure and plasma concentrations, steroids can exert either protective or adverse effects on neural tissues [120], [121], [122], [167], [223], [253], [348], [382], [471], [481], [662], [682], [687], [712], [713], [714], [843], [844], [845]. It has long been thought that steroidogenic glands, including the adrenal cortex, gonads and placenta, were the only sources of steroids that could act on the brain. However, seminal observations made by the group of Baulieu and Robel have shown that this view is incorrect. First, these authors discovered that the concentration of several steroids, notably pregnenolone (Δ5P), dehydroepiandrosterone (DHEA) and their sulfate esters Δ5P sulfate (Δ5PS) and DHEA sulfate (DHEAS), are much higher in the brain than in the plasma [55], [151], [152]. Second, they showed that the levels of these steroids in brain tissue remain elevated long after adrenalectomy and castration [125], [151], [152]. Third, they found that the circadian variations of steroid concentrations in brain tissue are not synchronized with those of circulating steroids [624]. These observations led them to propose that the brain could actually synthesize biologically active steroids, and they coined the term “neurosteroids” to designate these brain-born neuroactive steroids [57], [58], [623], [626].
The concept of neurosteroidogenesis has been subsequently substantiated by two sets of observations. (i) The occurrence of steroidogenic enzymes or their mRNAs has been evidenced, respectively, by immunohistochemistry or in situ hybridization studies, either in neurons or in glial cells, depending on the species and the enzyme considered [486], [487], [492], [493], [494], [495], [524], [623], [625], [626], [720], [745], [782], [792]. (ii) The corresponding enzymatic activities were demonstrated through the ability of brain tissue to convert tritiated precursors such as cholesterol or 5P into radioactive metabolites including 7α-hydroxypregnenolone (7αΟΗ-Δ5P), 17-hydroxypregnenolone (17OH-5P), progesterone (P), 17-hydroxyprogesterone (17OH-P), DHEA, 7α-hydroxydehydroepiandrosterone (7αOH-DHEA), dihydroprogesterone (DHP), tetrahydroprogesterone (THP, allopregnanolone), Δ5PS and DHEAS [54], [61], [141], [177], [304], [325], [454], [455], [456], [486], [492], [493], [494], [495], [775], [779], [780], [781], [785], [792], [793].
Concurrently, it became clear that neurosteroids exert a large array of biological activities in the brain [65], [382], [431], [568], [739] either through a conventional genomic action or through interaction with membrane receptors. In particular, neurosteroids have been found to act as allosteric modulators of the GABAA/central-type benzodiazepine receptor complex [64], [65], [156], [380], [431], NMDA receptors [317], [436], [448], [449], [485], [513], kainate receptors [154], [181], AMPA receptors [181], [648], [649], sigma receptors [278], [459], [460], [461], [462], [512], [738], [746], [796], glycine receptors [63], [78], [322], [432], [508], [850], serotonin receptors [366], [693], [694], nicotinic receptors [20], [101], [561], [584], [800] and muscarinic receptors [295], [358], [725]. More recently, it has been found that neurosteroids may directly activate G protein-coupled membrane receptors [205], [274], [279], [421], [500], [552], [667], [751], [790], [791], [876], [877] or indirectly modulate the binding of neuropeptides to their receptors [252], [414], [742], [768], [884]. Finally, neurosteroids have been shown to bind to microtubule-associated protein 2 and to stimulate tubulin polymerization in cultured neurons [310], [390], [526], [597].
In vivo studies also indicate that neurosteroids are involved in the regulation of various neurophysiological and behavioral processes, including cognition, arousal, stress, depression, anxiety and sleep, as well as in sexual- and feeding-related behaviors and locomotion [57], [83], [158], [180], [181], [182], [191], [208], [209], [264], [431], [463], [464], [489], [490], [501], [509], [594], [614], [683], [726], [739], [804], [805], [808]. Paradoxically, in spite of the evidence that locally produced steroids play a major role as signaling molecules within the brain, to date, little is known regarding the neural mechanisms regulating neurosteroid biosynthesis in the CNS. However, recent studies performed mainly in amphibians and birds have shown that the production of neurosteroids is finely regulated by neurotransmitters and neuropeptides.
The aim of the present review is to summarize the current knowledge regarding the distribution of steroidogenic enzymes, the biosynthesis of endogenous steroids and the regulation of their production in the CNS of vertebrates.
Section snippets
Neurosteroid biosynthesis in the vertebrate brain
The main criterion supporting the concept of neurosteroidogenesis is based upon the occurrence of biologically active steroidogenic enzymes in neural tissues. The presence of several key steroidogenic enzymes has now been demonstrated in the brain of vertebrates by immunohistochemistry and/or in situ hybridization (Table 1). These include the steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase/Δ5–Δ4 isomerase (3β-HSD),
Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides
As indicated above, it is now firmly established that, in all classes of vertebrates, the brain has the capability of synthesizing de novo biologically active steroids from cholesterol. There is also clear evidence that these brain-born steroids play important roles in the control of behavioral and neurophysiological processes such as learning, stress, anxiety, depression, sleep, sexual activity and food consumption. Surprisingly, however, in mammals, little is known regarding the neuronal
Unresolved issues and future perspectives
The basic observation that certain biologically active steroids are present in higher concentrations in the CNS than in blood, made by the group of Baulieu almost three decades ago [55], [151], [152], has been a major breakthrough. Since then, most enzymes responsible for the biosynthesis of steroids have been localized in the brain of many representative species of vertebrates (Table 1), and the occurrence of the corresponding enzymatic activities in brain tissue has been demonstrated.
Acknowledgments
This work was supported by grants from the Institut National de la Santé et de la Recherche Médical (Inserm U413), The Ministère des Affaires Etrangères (France-Québec exchange Program No. PV-P-73-9 to G.P. and H.V.), a France-Québec exchange program (Inserm-Fonds de la Recherche en Santé du Québec, FRSQ to G.P. and H.V.), France–Korean exchange programs (Inserm-Korea Science and Engineering Foundation, KOSEF to J.Y.S. and H.V.; and Science and Technology Amical Research, STAR to J.L.D.R.,
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Part of this review has been presented as the Geoffrey Harris Prize for Neuroendocrinology, Budapest, 2007.