Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination
- PMID:15135772
- DOI: 10.1016/j.ghir.2004.03.007
Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination
Abstract
Progesterone (PROG) is synthesized in the brain, spinal cord and peripheral nerves. Its direct precursor pregnenolone is either derived from the circulation or from local de novo synthesis as cytochrome P450scc, which converts cholesterol to pregnenolone, is expressed in the nervous system. Pregnenolone is converted to PROG by 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In situ hybridization studies have shown that this enzyme is expressed throughout the rat brain, spinal cord and dorsal root ganglia (DRG) mainly by neurons. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity to synthesize PROG, but expression and activity of 3beta-HSD in these cells are regulated by cellular interactions. Thus, Schwann cells convert pregnenolone to PROG in response to a neuronal signal. There is now strong evidence that P450scc and 3beta-HSD are expressed in the human nervous system, where PROG synthesis also takes place. Although there are only a few studies addressing the biological significance of PROG synthesis in the brain, the autocrine/paracrine actions of locally synthesized PROG are likely to play an important role in the viability of neurons and in the formation of myelin sheaths. The neuroprotective effects of PROG have recently been documented in a murine model of spinal cord motoneuron degeneration, the Wobbler mouse. The treatment of symptomatic Wobbler mice with PROG for 15 days attenuated the neuropathological changes in spinal motoneurons and had beneficial effects on muscle strength and the survival rate of the animals. PROG may exert its neuroprotective effects by regulating expression of specific genes in neurons and glial cells, which may become hormone-sensitive after injury. The promyelinating effects of PROG were first documented in the mouse sciatic nerve and in co-cultures of sensory neurons and Schwann cells. PROG also promotes myelination in the brain, as shown in vitro in explant cultures of cerebellar slices and in vivo in the cerebellar peduncle of aged rats after toxin-induced demyelination. Local synthesis of PROG in the brain and the neuroprotective and promyelinating effects of this neurosteroid offer interesting therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, for accelerating regenerative processes and for preserving cognitive functions during aging.
Similar articles
- Progesterone modulates brain-derived neurotrophic factor and choline acetyltransferase in degenerating Wobbler motoneurons.Gonzalez Deniselle MC, Garay L, Gonzalez S, Saravia F, Labombarda F, Guennoun R, Schumacher M, De Nicola AF.Gonzalez Deniselle MC, et al.Exp Neurol. 2007 Feb;203(2):406-14. doi: 10.1016/j.expneurol.2006.08.019. Epub 2006 Oct 17.Exp Neurol. 2007.PMID:17052708
- Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord.González SL, Labombarda F, González Deniselle MC, Guennoun R, Schumacher M, De Nicola AF.González SL, et al.Neuroscience. 2004;125(3):605-14. doi: 10.1016/j.neuroscience.2004.02.024.Neuroscience. 2004.PMID:15099674
- Progesterone: therapeutic opportunities for neuroprotection and myelin repair.Schumacher M, Guennoun R, Stein DG, De Nicola AF.Schumacher M, et al.Pharmacol Ther. 2007 Oct;116(1):77-106. doi: 10.1016/j.pharmthera.2007.06.001. Epub 2007 Jun 18.Pharmacol Ther. 2007.PMID:17659348Review.
- Effect of streptozotocin-induced diabetes on the gene expression and biological activity of 3beta-hydroxysteroid dehydrogenase in the rat spinal cord.Saredi S, Patte-Mensah C, Melcangi RC, Mensah-Nyagan AG.Saredi S, et al.Neuroscience. 2005;135(3):869-77. doi: 10.1016/j.neuroscience.2005.06.033. Epub 2005 Aug 19.Neuroscience. 2005.PMID:16111823
- Progesterone and the spinal cord: good friends in bad times.Labombarda F, González Deniselle MC, De Nicola AF, González SL.Labombarda F, et al.Neuroimmunomodulation. 2010;17(3):146-9. doi: 10.1159/000258709. Epub 2010 Feb 4.Neuroimmunomodulation. 2010.PMID:20134188Review.
Cited by
- Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer's Disease Diagnosis.Rammouz G, Lecanu L, Papadopoulos V.Rammouz G, et al.Front Endocrinol (Lausanne). 2011 Nov 8;2:69. doi: 10.3389/fendo.2011.00069. eCollection 2011.Front Endocrinol (Lausanne). 2011.PMID:22654823Free PMC article.
- Neurosteroids, trigger of the LH surge.Kuo J, Micevych P.Kuo J, et al.J Steroid Biochem Mol Biol. 2012 Aug;131(1-2):57-65. doi: 10.1016/j.jsbmb.2012.01.008. Epub 2012 Feb 2.J Steroid Biochem Mol Biol. 2012.PMID:22326732Free PMC article.
- Myelin pathogenesis and functional deficits following SCI are age-associated.Siegenthaler MM, Ammon DL, Keirstead HS.Siegenthaler MM, et al.Exp Neurol. 2008 Oct;213(2):363-71. doi: 10.1016/j.expneurol.2008.06.015. Epub 2008 Jul 3.Exp Neurol. 2008.PMID:18644369Free PMC article.
- 3β-HSD expression in the CNS of a manakin and finch.Eaton J, Pradhan DS, Barske J, Fusani L, Canoine V, Schlinger BA.Eaton J, et al.Gen Comp Endocrinol. 2018 Jan 15;256:43-49. doi: 10.1016/j.ygcen.2017.09.016. Epub 2017 Sep 18.Gen Comp Endocrinol. 2018.PMID:28935582Free PMC article.
- The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression.Wang JM, Johnston PB, Ball BG, Brinton RD.Wang JM, et al.J Neurosci. 2005 May 11;25(19):4706-18. doi: 10.1523/JNEUROSCI.4520-04.2005.J Neurosci. 2005.PMID:15888646Free PMC article.
Publication types
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources