Abstract
Peripheral steroid hormones act on brain tissues through intracellular receptor-mediated mechanisms to regulate several important brain neuronal functions. The brain is therefore considered to be a target site of steroid hormones. In contrast to this classical concept, new findings over the past decade have established that the brain itself also synthesizes steroids de novo from cholesterol through mechanisms at least partly independent of peripheral steroidogenic glands. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To analyze neurosteroid actions in the brain, we need data on the specific synthesis in particular sites of the brain at particular times. Such information is crucial to developing hypotheses predicting the potential roles of particular neurosteroids in the developing and adult brains. Thus our studies for this exciting area of brain research have focused on the biosynthesis of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Purkinje cell, a typical cerebellar neuron, is a major site for neurosteroid formation in the brain. This is the first observation of neuronal neurosteroidogenesis in the brain. Subsequently genomic and nongenomic actions of neurosteroids have been suggested by a series of our studies using an excellent Purkinje cellular model. Here we summarize the advances made in our understanding of biosynthesis of neurosteroids in the cerebellar Purkinje cell.
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References
Fuxe K, Gustafsson JA, Wetterberg L. Steroid Hormone Regulation of the Brain. Oxford: Pergamon Press, 1981.
Arnold AP, Gorski RA. Gonadal steroid induction of structural sex differences in the CNS. Annu Rev Neurosci 1984; 7: 413–442.
McEwen BS. Steroid hormones are multifunctional messengers in the brain. Trends Endocrinol Metab 1991; 2: 62–67.
Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system (review). Rec Prog Hormone Res 1997; 52: 1–32.
Tsutsui K, Ukena K, Takase M, Kohchi C, Lea RW. Neurosteroid biosynthesis in vertebrate brains (review). Comp Biochem Physiol C 1999; 124: 121–129.
Tsutsui K, Ukena K, Usui M, Sakamoto H, Takase M. Novel brain function: biosynthesis and actions of neurosteroids in neurons (review). Neurosci Res 2000; 36: 261–273.
Compagnone NA, Mellon SH. Neurosteroids: biosynthesis and function of these novel neuromodulators (review). Frontiers Neuroendocrinol 2000; 21: 1–56.
Tsutsui K. Biosynthesis and biological actions of neurosteroids in brain neurons (review). Zool Sci 2001; 18: 1043–1053.
Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE. Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA 1981; 78: 4704–4707.
Corpéchot C, Synguelakis M, Talha S, et al. Pregnenolone and its sulfate ester in rat brain. Brain Res 1983; 270: 119–125.
Robel P, Baulieu EE. Neuro-steroids, 3β-hydroxy-Δ5-derivatives in the rodent brain. Neurochem Int 1985; 7: 953–958.
Lanthier A, Patwardhan VV. Sex steroids and 5-en-3β-hydroxysteroids in specific regions of the human brain and cranial nerves. J Steroid Biochem 1986; 25: 445–449.
Robel P, Corpéchot C, Clarke C, et al. Neuro-steroids: 3β-hydroxy-Δ5-derivatives in the rat brain. In: Fink G, Harmar AJ, McKerns KW, editors. Neuroendocrine Molecular Biology. New York: Plenum Press, 1986: 367–377.
Robel P, Bourreau E, Corpéchot C, et al. Neuro-steroids: 3β-hydroxy-Δ5-derivatives in rat and monkey brain. J Steroid Biochem 1987; 27: 649–655.
Jo DH, Abdallah MA, Young J, Baulieu EE, Robel P. Pregnenolone, dehydroepiandrosterone, and their sulfate and fatty acid esters in the rat brain. Steroids 1989; 54: 287–297.
Mathur C, Prasad VVK, Raju VS, Welch M, Lieberman S. Steroids and their conjugates in the mammalian brain. Proc Natl Acad Sci USA 1993; 90: 85–88.
Tsutsui K, Yamazaki T. Avian neurosteroids. I. Pregnenolone biosynthesis in the quail brain. Brain Res 1995; 678: 1–9.
Usui M, Yamazaki T, Kominami S, Tsutsui K. Avian neurosteroids. II. Localization of a cytochrome P450scc-like substance in the quail brain. Brain Res 1995; 678: 10–20.
Tsutsui K, Yamazaki T, Usui M, et al. P450scc activity in the brain. In: Harvey S, Etches RJ, editors. Perspectives in Avian Endocrinology. Bristol: Journal of Endocrinology Ltd, 1997: 427–436.
Tsutsui K, Usui M, Yamazaki T, Ukena K, Kominami S. Neurosteroids in the avian brain. In: Maitra SK, editor. Frontiers in Environmental and Metabolic Endocrinology. Burdwan: Burdwan Press, 1997: 151–159.
Ukena K, Honda Y, Inai Y, Kohchi C, Lea RW, Tsutsui K. Expression and activity of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in different regions of the avian brain. Brain Res 1999; 818: 536–542.
Ukena K, Honda Y, Lea RW, Tsutsui K. Developmental changes in progesterone biosynthesis and metabolism in the quail brain. Brain Res 2001; 898: 190–194.
Matsunaga M, Ukena K, Tsutsui K. Expression and localization of cytochrome P450 17α-hydroxylase/c17, 20-lyase in the avian brain. Brain Res 2001; 899: 112–122.
Matsunaga M, Ukena K, Tsutsui K. Androgen biosynthesis in the quail brain. Brain Res 2002; 948: 180–185.
Tsutsui K, Schlinger BA. Steroidogenesis in the avian brain. In: Dawson A, Chaturvedi CM, editors. Avian Endocrinology. New Delhi: Narosa Publishing House, 2001: 59–77.
Takase M, Ukena K, Yamazaki T, Kominami S, Tsutsui K. Pregnenolone, pregnenolone sulfate and cytochrome P450 sidechain cleavage enzyme in the amphibian brain and their seasonal changes. Endocrinology 1999; 140: 1936–1944.
Sakamoto H, Ukena K, Tsutsui K. Activity and localization of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in the zebrafish central nervous system. J Comp Neurol 2001; 439: 291–305.
Mensah-Nyagan AG, Feuilloley M, Dupont E, et al. Immuno-cytochemical localization and biological activity of 3β-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci 1994; 14: 7306–7318.
Mensah-Nyagan AG, Feuilloley M, Do-Rego JL, et al. Localization of 17β-hydroxysteroid dehydrogenase and characterization of testosterone in the brain of the male frog. Proc Natl Acad Sci USA 1996; 93: 1423–1428.
Mensah-Nyagan AG, Do-Rego JL, Feuilloley M, et al. In vivo and in vitro evidence for the biosynthesis of testosterone in the telencephalon of the female frog. J Neurochem 1996; 67: 413–422.
Vanson A, Arnold AP, Schlinger BA. 3β-Hydroxysteroid dehydrogenase/isomerase and aromatase activity in primary cultures of developing zebra finch telencephalon: dehydroepiandrosterone as substrate for synthesis of androstenedione and estrogens. Gen Comp Endocrinol 1996; 102: 342–350.
Schlinger BA, Lane NI, Grisham W, Thompson L. Androgen synthesis in a songbird: a study of cyp 17 (17α-hydroxylase/c 17,20-lyase) activity in the zebra finch. Gen Comp Endocrinol 1999; 113: 46–58.
Freking F, Nazairians T, Schlinger BA. The expression of the sex steroid-synthesizing enzymes CYP11A1, 3β-HSD, CYP17, and CYP 19 in gonads and adrenals of adult and developing zebra finches. Gen Comp Endocrinol 2000; 119: 140–151.
Ukena K, Usui M, Kohchi C, Tsutsui K. Cytochrome P450 sidechain cleavage enzyme in the cerebellar Purkinje neuron and its neonatal change in rats. Endocrinology 1998; 139: 137–147.
Ukena K, Kohchi C, Tsutsui K. Expression and activity of 3βhydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in the rat Purkinje neuron during neonatal life. Endocrinology 1999; 140: 805–813.
Hu ZY, Bourreau E, Jung-Testas I, Robel P, Baulieu EE. Neurosteroids: oligodendrocyte mitochondria convert cholesterol to pregnenolone. Proc Natl Acad Sci USA 1987; 84: 8215–8219.
Le Goascogne C, Robel P, Gouézou M, Sananès N, Baulieu EE, Waterman M. Neurosteroids: cytochrome P-450scc in rat brain. Science 1987; 237: 1212–1215.
Jung-Testas I, Hu ZY, Baulieu EE, Robel P. Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology 1989; 125: 2083–2091.
Iwahashi K, Ozaki HS, Tsubaki M, Ohnishi J, Takeuchi Y, Ichikawa Y. Studies of the immunohistochemical and biochemical localization of the cytochrome P-450scc-linked monooxygenase system in the adult rat brain. Biochim Biophys Acta 1990; 1035: 182–189.
Papadopoulos V, Guarneri P, Krueger KE, Guidotti A, Costa E. Pregnenolone biosynthesis in C6-2B glioma cell mitochondria: Regulation by a mitochondrial diazepam binding inhibitor receptor. Proc Natl Acad Sci USA 1992; 89: 5113–5117.
Mellon SH, Deschepper CF. Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 1993; 629: 283–292.
Compagnone NA, Bulfone A, Rubenstein JLR, Mellon SH. Steroidogenic enzyme P450cl7 is expressed in the embryonic central nervous system. Endocrinology 1995; 136: 5212–5223.
Baulieu EE, Robel P. Neurosteroids: A new brain function? J Steroid Biochem Mol Biol 1990; 37: 395–403.
Baulieu EE. Neurosteroids: a new function in the brain. Biol Cell 1991; 71: 3–10.
Kohchi C, Ukena K, Tsutsui K. Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes P450scc, P450c17 and 3β-HSD in the postnatal rat brain. Brain Res 1998; 801: 233–238.
Zwain IH, Yen SSC. Dehydroepiandrosterone: biosynthesis and metabolism in the brain. Endocrinology 1999; 140: 880–887.
Mason JI. The 3β-hydroxysteroid dehydrogenase gene family of enzymes. Trends Endocrinol Metab 1993; 4: 199–203.
Dupont E, Simard J, Luu-The V, Labrie F, Pelletier G. Localization of 3β-hydroxysteroid dehydrogenase in rat brain as studied by in situ hybridization. Mol Cell Neurosci 1994; 5: 119–123.
Guennoun R, Fiddes RJ, Gouézou M, Lombès M, Baulieu EE. A key enzyme in the biosynthesis of neurosteroids, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD), is expressed in rat brain. Mol Brain Res 1995; 30: 287–300.
Sanne JL, Krueger KE. Expression of cytochrome P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase in the rat central nervous system: a study by polymerase chain reaction and in situ hybridization. J Neurochem 1995; 65: 528–536.
Weidenfeld J, Siegel RA, Chowers I. In vitro conversion of pregnenolone to progesterone by discrete brain areas of the male rat. J Steroid Biochem 1980; 13: 961–963.
Akwa Y, Sananès N, Gouézou M, Robel P, Baulieu EE, Le Goascogne C. Astrocytes and neurosteroids: metabolism of pregnenolone and dehydroepiandrosterone. Regulation by cell density. J Cell Biol 1993; 121: 135–143.
Kabbadj K, El-Etr M, Baulieu EE, Robel P. Pregnenolone metabolism in rodent embryonic neurons and astrocytes. Glia 1993; 7: 170–175.
Clark JA, Tsutsui K, Ukena K, Lea RW. Changes in central progesterone during the reproductive cycle of the ring dove (Streptopelia risoria). 15th National Meeting of the British Neuroscience Association, Harrogate, UK, 1999; (Suppl): 15.
Lea RW, Clark JA, Tsutsui K. Changes in central steroid receptor expression, steroid synthesis and dopaminergic activity related to the reproductive cycle of the ring dove (review). Microsc Res Tech 2001; 55: 12–26.
Pignataro L, Lerner AAC, Baranao JL, de Plazas SF. Biosynthesis of progesterone derived neurosteroids by developing avian CNS: in vitro effects on the GABAA receptor complex. Int J Dev Neurosci 1998; 16: 433–441.
Strömstedt M, Waterman MR. Messenger RNAs encoding steroidogenic enzymes are expressed in rodent brain. Mol Brain Res 1995; 34: 75–88.
Akwa Y, Young J, Kabbadj K, et al. Neurosteroids: Biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. J Steroid Biochem Mol Biol 1991; 40: 71–81.
Furukawa A, Miyatake A, Ohnishi T, Ichikawa Y. Steroidogenic acute regulatory protein (StAR) transcripts constitutively expressed in the adult rat central nervous system: Colocalization of StAR, cytochrome P-450scc (CYP XIA1), and 3β-hydroxysteroid dehydrogenase in the rat brain. J Neurochem 1998; 71: 2231–2238.
Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 1994; 269: 28314–28322.
Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996; 17: 221–244.
Tsutsui K, Ukena K. Neuronal neurosteroidogenesis in the cerebellum. In: Okamoto M, Ishimura Y, Nawata H, editors. Molecular Steroidogenesis. Tokyo: Universal Academy Press, 2000: 397–400.
Tsutsui K, Ukena K, Sakamoto H. Novel cerebellar function: neurosteroids in the Purkinje neurons and their genomic and nongenomic actions. In: Handa RJ, Hayashi S, editors. Neuroplasticity, Development, and Steroid Hormone Action. Boca Raton: CRC Press, 2001: 101–116.
Tsutsui K, Ukena K. Neurosteroids in the cerebellar Purkinje neuron and their actions (review). Int J Mol Med 1999; 4: 49–56.
Airman J. Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol 1972; 145: 353–397.
Airman J. Postnatal development of the cerebellar cortex in the rat. II. Phases in the maturation of Purkinje cells and of the molecular layer. J Comp Neurol 1972; 145: 399–463.
Sakamoto H, Ukena K, Tsutsui K. Effects of progesterone synthesized de novo in the developing Purkinje cell on its dendritic growth and synaptogenesis. J Neurosci 2001; 21: 6221–6232.
Sakamoto H, Ukena K, Tsutsui K. Dendritic spine formation in response to progesterone synthesized de novo in the developing Purkinje cell in rats. Neurosci Lett 2002; 322: 111–115.
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Tsutsui, K., Sakamoto, H. & Ukena, K. A novel aspect of the cerebellum: biosynthesis of neurosteroids in the Purkinje cell. Cerebellum 2, 215–222 (2003). https://doi.org/10.1080/14734220310016169
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DOI: https://doi.org/10.1080/14734220310016169