Summary
1. Some progesterone is synthesized within both the central and the peripheral nervous systems, where it regulates neurotransmission and important glial functions, such as the formation of myelin. Progesterone can thus be designated a “neurosteroid.”
2. Steroids act not only on the brain, but also on peripheral nerves, which offer many advantages to study the biological significance of locally produced neurosteroids: their remarkable plasticity and regenerative capacity and their relatively simple structure.
3. By using the regenerating mouse sciatic nerve as a model, we have shown that progesterone synthesized by rat Schwann cells promotes the formation of new myelin sheaths. Progesterone also increases the number of myelinated axons when added at a low concentration to cocultures of Schwann cells and sensory neurons.
4. These findings show a function on myelination for locally produced progesterone and suggest a new pharmacological approach of myelin repair.
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References
Akwa, Y., Schumacher, M., Jung-Testas, I., and Baulieu, E. E. (1993a). Neurosteroids in rat sciatic nerves and Schwann cells.C.R. Acad. Sci. (III) (Paris) 316410–414.
Akwa, Y., Sananès, N., Robel, P., Baulieu, E. E., and Le Goascogne, C. (1993b). Astrocytes and neurosteroids: Metabolism of pregnenolone and dehydroepianodrosterone. Regulation by cell density.J. Cell Biol. 121135–143.
Baulieu, E. E. (1981). Steroid hormones in the brain: Several mechanisms? InSteroid Hormone Regulation of the Brain (K. Fuxe, J. A. Gustafsson, and L. Wetterberg, Eds.), Pergamon Press, Oxford, pp. 3–14.
Baulieu, E. E. (1991). Neurosteroids: A new function in the brain.Biol. Cell. 713–10.
Bizzozero, O. A., and Good, L. K. (1991). Rapid metabolism of fatty acids covalently bound to myelin proteolipid protein.J. Biol. Chem. 26617092–17098.
Bolin, L. M., and Shooter, E. M. (1993). Neurons regulate Schwann cell genes by diffusible molecules.J. Cell Biol. 123237–243.
Chadwick, D., and Widdows, K. (1990).Steroids and Neuronal Activity (Ciba Found. Symp. 153), Wiley, Chichester.
Corpéchot, C., Synguelakis, M., Talha, S., Axelson, M., Sjövall, J., Vihko, R., Baulieu, E. E., and Robel, P. (1983). Pregnenolone and its sulfate ester in the rat brain.Brain Res. 270119–125.
Droz, B., Di Giamberardino, L., and Koenig, H. L. (1981). Contribution of axonal transport to the renewal of myelin phospholipids in peripheral nerves. I. Quantitative radioautographic study.Brain Res. 21957–71.
Fawcett, J. W., and Keynes, R. J. (1990). Peripheral nerve regeneration.Annu. Rev. Neurosci. 1343–60.
Guennoun, R., Fiddes, R. J., Gouézou, M., Lombès, M., and Baulieu, E. E. (1995). A key enzyme in the biosynthesis of neurosteroids, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase(3β-HSD) is expressed in rat brain.Mol. Brain Res. (in press).
Guth, L., Zhang, Z., and Roberts, E. (1994). Key role for pregnenolone in combination therapy promotes recovery after spinal cord injury.Proc. Natl. Acad. Sci. USA 9112308–12312.
Hildebrand, C., Bowe, C. M., and Nilsson Remahl, I. (1994). Myelination and myelin sheath remodelling in normal and pathological PNS nerve fibers.Prog. Neurobiol. 4385–141.
Jay, J. R., MacLaughlin, D. T., Badger, T. M., Miller, D. C., and Martuza, R. L. (1986). Hormonal modulation of Schwann cell tumors.Ann. N.Y. Acad. Sci. 486371–382.
Jung-Testas, I., Hu, Z. Y., Robel, P., and Baulieu, E. E. (1989). Biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells.Endocrinology 1252083–2091.
Jung-Testas, I., Schumacher, M., Bugnard, H., and Baulieu, E. E. (1993). Stimulation of rat Schwann cell proliferation by estradiol: Synergism between the estrogen and cAMP.Dev. Brain Res. 72282–290.
Jung-Testas, I., Schumacher, M., Robel, P., and Baulieu, E. E. (1994). Actions of steroid hormones and growth factors on glial cells of the central and peripheral nervous system.J. Steroid Biochem. Mol. Biol. 48145–154.
Jurevics, H., and Morell, P. (1994). Sources of cholesterol for kidney and nerve during development.J. Lipid Res. 35112–120.
Jurevics, H., and Morell, P. (1995). Cholesterol for synthesis of myelin is made locally, not imported into brain.J. Neurochem. 64895–901.
Kabbadj, K., EL-Etr, M., Baulieu, E. E., and Robel, P. (1993). Pregnenolone metabolism in rodent embryonic neurons and astrocytes.Glia 7170–175.
Koenig, H., Schumacher, M., Ferzaz, B., Do Thi, N. A., Ressouches, A., Guennoun, R., Jung-Testas, I., Robel, P., Akwa, Y., and Baulieu, E. E. (1995). Progesterone synthesis and myelin formation by Schwann cells.Science (in press).
Lan, N. C., Gee, K. W., Bolger, M. B., and Chen, J. S. (1991). Differential responses of expressed recombinant human gamma-aminobutyric acid A receptors to neurosteroids.J. Neurochem. 571818–1821.
Le Goascogne, C., Robel, P., Gouézou, M., Sananès, N., Baulieu, E. E., and Waterman, M. (1987). Neurosteroids: Cytochrome P450scc in rat brain.Science 2371212–1215.
Lemke, G., Weinmaster, G., and Monuki, E. S. (1990). The myelination cascade. InCellular and Molecular Biology of Myelination (G. Jeserich, H. H. Althaus, and T. V. Waehneldt, Eds.), Springer Verlag, Berlin, pp. 533–541.
Léna, C., and Changeux, J. P. (1993). Allosteric modulations of the nicotinic acetylcholine receptor.Trends Neurosci. 16181–186.
Magoffin, D. A., Kurtz, K. M., and Erickson, G. F. (1990). Insulin-like growth factor-I selectively stimulates cholesterol side-chain cleavage expression in ovarian theca-interstitial cells.Mol. Endocrinol. 4489–496.
Majewska, M. D. (1992). Neurosteroids: Endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance.Prog. Neurobiol. 38379–395.
Mason, J. I. (1993). The 3β-hydroxysteroid dehydrogenase gene family of enzymes.Trends Endocrinol. Metab. 4199–203.
McEwen, B. S., Coirini, H., and Schumacher, M. (1990). Steroid effects on neuronal activity: When is the genome involved? InSteroids and Neuronal Activity (D. Chadwick and K. Widdows, Eds.), Ciba Found. Symp. 153, John Wiley & Sons, Chichester, pp. 3–21.
Mellon, S. H. (1994). Neurosteroids: Biochemistry, modes of action, and clinical relevance.J. Clin. Endocrinol. Metab. 781003–1008.
Mellon, S. H., and Deschepper, C. F. (1993). Neurosteroid biosynthesis: Genes for adrenal steroidogenic enzymes are expressed in the brain.Brain Res. 629283–292.
Monnet, F. P., Mahé, V., Rohel, P., and Baulieu, E. E. (1995). Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.Proc. Natl. Acad. Sci. USA (in press).
Morfin, R., Young, J., Corpéchot, C., Egestad, B., Sjövall, J., and Baulieu, E. E. (1992). Neurosteroids: Pregnenolone in human sciatic nerves.Proc. Natl. Acad. Sci. USA 896790–6793.
Neuberger, T. J., Kalimi, O., Regelson, W., Kalimi, M., and De Vries, G. H. (1994). Glucocorticoids enhance the potency of Schwann cell mitogens.J. Neurosci. Res. 38300–313.
Oonk, R. B., Krasnow, J. S., Beattie, W. G., and Richards, J. S. (1989). Cyclic AMP-dependent and -independent regulation of cholesterol side chain cleavage cytochrome P-450 (P-450scc) in rat ovarian granulosa cells and copora lutea.J. Biol. Chem. 26421934–21942.
Paul, S. M., and Purdy, R. H. (1992). Neuroactive steroids.FASEB J. 62311–2322.
Roa, B. B., Garcia, C. A., Pentao, L., Killina, J. M., Trask, B. J., Suter, U., Snipes, G. J., Ortiz-Lopez, R., Shooter, E. M., and Patel, P. I. (1993). Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A.Nat. Genet. 5189–194.
Robel, P., and Baulieu, E. E. (1985). Neurosteroids: 3β-Hydrox-Δ5-derivatives in the rodent brain.Neurochem. Int. 7953–958.
Robel, P., and Baulieu, E. E. (1994). Neurosteroids. Biosynthesis and function.Trends Endocrinol. Metab. 51–8.
Schaeffer, C., and Aron, C. (1987). Stress-related effects on the secretion of progesterone by the adrenals in castrated male rats presented to stimulus males. Involvement of oestrogenActa Endocrinol. 114440–445.
Schumacher, M., Coirini, H., Pfaff, D. W., and McEwen, B. S. (1990). Behavioral effects of progesterone associated with rapid modulation of oxytocin receptors.Science 250691–694.
Schumacher, M., Jung-Testas, I., Robel, P., and Baulieu, E. E. (1993). Insulin-like growth factor I: A mitogen for rat Schwann cells in the presence of elevated levels of cyclic AMP.Glia 8232–240.
Shingai, R., Sutherland, M. L., and Barnard, E. A. (1991). Effects of subunit types of the cloned GABAA receptor on the response to a neurosteroid.Eur. J. Pharmacol. 20677–80.
Snipes, J. G., Suter, U., and Shooter, E. M. (1993). The genetics of myelin.Curr. Opin. Neurobiol. 3694–702.
Suter, U., Welcher, A. A., Ozcelik, T., Snipes, G. J., Kosaras, B., Francke, U., Billings-Gagliardi, S., Sidman, R. L., and Shooter, E. M. (1992). Trembler mouse carries a point mutation in a myelin gene.Nature 356241–244.
Toews, A. D., Armstrong, R., Gould, R. M., and Morell, P. (1988). Deposition and transfer of axonally transported phospholipids in rat sciatic nerve.J. Neurosci. 8593–601.
Valera, S., Ballivet, M., and Bertrand, D. (1992). Progesterone modualtes a neuronal nicotinic acetylcholine receptor.Proc. Natl. Acad. Sci. 899949–9953.
Warembourg, M., Otten, U., and Schwab, M. E. (1981). Labelling of Schwann and satellite cells by [3H]dexamethasone in a rat sympathetic ganglion and sciatic nerve.Neuroscience 61139–1143.
Woolley, C. S., and Gould, E. (1994). Steroid action on neuronal structure. InNeurobiology of Steroids.Methods in Neurosciences, Vol.22, (R. E. De Kloet and W. Sutanto, Eds.), Academic Press, San Diego, pp. 383–402.
Yu, W. H. (1989). Survival of motoneurons following axotomy is enhanced by lactation or by progesterone treatment.Brain Res. 491379–382.
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Baulieu, E.E., Schumacher, M., Koenig, H. et al. Progesterone as a neurosteroid: Actions within the nervous system. Cell Mol Neurobiol 16, 143–154 (1996). https://doi.org/10.1007/BF02088173
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DOI: https://doi.org/10.1007/BF02088173