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Michael Schumacher - One of the best experts on this subject based on the ideXlab platform.
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progesterone synthesis metabolism mechanisms of action and effects in the nervous system an overview
Hormones brain and behavior, 2009Co-Authors: Michael Schumacher, R GuennounAbstract:Over the past few years, we have witnessed much progress in our understanding of the synthesis, mechanisms of actions, and effects of progesterone in the nervous system. This hormone, well known for its role in pregnancy, regulates many reproductive functions, including sexual behavior in both females and males and the release of gonadotropins. In addition, progesterone exerts marked influences on diverse neural cell functions throughout the nervous system. Studies on the nonreproductive functions of progesterone and its metabolites in the brain have mainly focused on the modulation of neurotransmission, and in particular on the effects of 3α,5α-Tetrahydroprogesterone (allopregnanolone) on GABA-A receptors. Recent experimental studies have shown that progesterone also plays an important role in the viability and regeneration of neurons and in the formation of myelin sheaths. However, we still know very little about the mechanisms by which progesterone exerts its multiple effects in the nervous system. Progesterone present in nervous tissues is not only derived from the steroidogenic endocrine glands, but it can also be synthesized by neurons and glial cells. The significance of the local synthesis of progesterone in the brain, spinal cord, and peripheral nerves remains to be elucidated, but it is likely to play an important role in autocrine/paracrine signaling mechanisms.
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injury elicited increase in spinal cord neurosteroid content analyzed by gas chromatography mass spectrometry
Endocrinology, 2006Co-Authors: Florencia Labombarda, Antoine Pianos, Philippe Liere, Bernard Eychenne, S L Gonzalez, Annie Cambourg, A F De Nicola, Michael SchumacherAbstract:The effects of spinal cord injury (SCI), combined with castration and adrenalectomy, and of progesterone (PROG) treatment on neurosteroid levels and steroidogenic enzyme expression were investigated in the adult male rat spinal cord (SC). Steroid levels were quantified by gas chromatography/mass spectrometry in SC and plasma, and mRNAs of enzymes by quantitative real-time RT-PCR. The levels of pregnenolone (PREG), PROG, 5alpha-dihydroprogesterone, 3alpha,5alpha-Tetrahydroprogesterone increased in SC 75 h after transection without significant increase in the plasma. After combined adrenalectomy and gonadectomy, significant levels of PREG and PROG remained in the SC, suggesting their local biosynthesis. In the SC of adrenalectomized and gonadectomized rats, there was an increase of PREG 24 h after SCI, followed at 75 h by a concomitant increase in its direct metabolite, PROG. These observations are consistent with a sequential increase of PREG biosynthesis and its conversion to PROG within the SC in response to injury. However, no significant change in P450-side chain cleavage and 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase mRNA levels was observed after SCI. Systemic PROG treatment after SCI, resulted in a very large increase in PROG, 5alpha-dihydroprogesterone, and 3alpha,5alpha-Tetrahydroprogesterone in both plasma and SC. Furthermore, high levels of 3beta,5alpha-Tetrahydroprogesterone were detected in SC, whereas their plasma levels remained barely detectable. Because the ratio of reduced metabolites to PROG was 65-times higher in SC than in the plasma, it appears likely that reduced metabolites mainly originated from local biosynthesis. Our results strongly suggest an important role for locally biosynthesized neurosteroids in the response of the SC to injury.
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3α 5α Tetrahydroprogesterone allopregnanolone and γ aminobutyric acid autocrine paracrine interactions in the control of neonatal psa ncam progenitor proliferation
Journal of Neuroscience Research, 2004Co-Authors: Nathalie Gago, Martine Eletr, N Sananes, Francoise Cadepond, Denise Samuel, Virginia Avellanaadalid, Anne Baronvan Evercooren, Michael SchumacherAbstract:The earliest identified neonatal neural progenitors are cells that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). One of these progenitors is the early PSA-NCAM+ progenitor (ePSA-NCAM+ progenitor; Gago et al. [2003] Mol Cell Neurosci 22:162-178), which corresponds to a multipotential cell with a default differentiation through glial lineages. The ePSA-NCAM+ progenitor can synthesize the neurosteroid progesterone (PROG) and its reduced metabolite 3alpha,5alpha-Tetrahydroprogesterone (3alpha,5alpha-THP, or allopregnanolone; Gago et al. [ 2001] Glia 36:295-308). The latter is a potent positive allosteric modulator of gamma-aminobutyric acid type A (GABAA) receptors. In the present work, we demonstrate that PROG and 3alpha,5alpha-THP both stimulate ePSA-NCAM+ progenitor proliferation. PROG exerted its mitogenic effect indirectly, through its conversion to 3alpha,5alpha-THP, since it could be abolished by an inhibitor of the 5alpha-reductase (L685-273) and mimicked by 3alpha,5alpha-THP. A dose-response curve revealed a bell-shaped effect of 3alpha,5alpha-THP on ePSA-NCAM+ progenitor proliferation, with greatest stimulation at nanomolar concentrations. The mitogenic effect of 3 alpha,5 alpha-THP was mediated by GABAA receptors, insofar as it could be blocked by the selective antagonist bicuculline. ePSA-NCAM+ progenitors indeed expressed mRNAs for GABAA receptor subunits, and GABA enhanced cell proliferation, an effect that was also bicuculline sensitive. Moreover, these cells synthesized GABA, which was involved in a tonic stimulation of their proliferation. These results reveal complex autocrine/paracrine loops in the control of ePSA-NCAM+ progenitor proliferation, involving both neurosteroid and GABA signaling, and suggest a novel key role for 3alpha,5alpha-THP in the development of the nervous system.
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progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum
Journal of Neurochemistry, 2003Co-Authors: Abdel M Ghoumari, Bernard Eychenne, Etienneemile Baulieu, Martine Eletr, C Ibanez, Philippe Leclerc, B W Omalley, Michael SchumacherAbstract:We have previously shown that progesterone (PROG) is synthesized by Schwann cells and promotes myelin formation in the peripheral nervous system (PNS). We now report that this neurosteroid also stimulates myelination in organotypic slice cultures of 7-day-old (P7) rat and mouse cerebellum. Myelination was evaluated by immunofluorescence analysis of the myelin basic protein (MBP). After 7 days in culture (7DIV), we found that adding PROG (2–5 × 10−5 M) to the culture medium caused a fourfold increase in MBP expression when compared to control slices. The effect of PROG on MBP expression involves the classical intracellular PROG receptor (PR): the selective PR agonist R5020 significantly increased MBP expression and the PR antagonist mifepristone (RU486) completely abolished the effect of PROG on this MBP expression. Moreover, treatment of P7-cerebellar slice cultures from PR knockout (PRKO) mice with PROG had no significant effect on MBP expression. PROG was metabolized in the cerebellar slices to 5α-dihydroprogesterone (5α-DHP) and to the GABAA receptor-active metabolite 3α,5α-Tetrahydroprogesterone (3α,5α-THP, allopregnanolone). The 5α-reductase inhibitor L685-273 partially inhibited the effect of PROG, and 3α,5α-THP (2–5 × 10−5 M) significantly stimulated the MBP expression, although to a lesser extent than PROG. The increase in MBP expression by 3α,5α-THP involved GABAA receptors, as it could be inhibited by the selective GABAA receptor antagonist bicuculline. These findings suggest that progestins stimulate MBP expression and consequently suggest an increase in CNS myelination via two signalling systems, the intracellular PR and membrane GABAA receptors, and they confirm a new role of GABAA receptors in myelination.
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progesterone and the oligodendroglial lineage stage dependent biosynthesis and metabolism
Glia, 2001Co-Authors: Etienneemile Baulieu, Yvette Akwa, Nathalie Gago, Martine Eletr, N Sananes, Rachida Guennoun, Michael SchumacherAbstract:Evidence has been accumulated showing that neurosteroids, particularly progesterone (PROG) and its metabolites, may participate in myelination and remyelination in the peripheral nervous system, but very few studies have been undertaken in the central nervous system (CNS). The aim of this work was to investigate the capacities of synthesis and metabolism of PROG at three important stages of the oligodendroglial lineage: oligodendrocyte pre-progenitors (OPP), oligodendrocyte progenitors (OP), and fully differentiated oligodendrocytes (OL). Experiments have been conducted in vitro using highly purified primary cell cultures from rat brain. Cells were incubated with (3)H-pregnenolone ((3)H-PREG), the immediate precursor of PROG, or with (3)H-PROG, and steroids metabolites were then identified by thin layer chromatography and high-performance liquid chromatography (HPLC). mRNA expression of key steroidogenic enzymes was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that only OPP and OP, but not OL, expressed 3 beta-hydroxysteroid dehydrogenase/Delta 5-Delta 4 isomerase mRNA and were able to synthesize PROG from PREG. In the three cell types studied, PROG was metabolized by the type 1 isoform of 5 alpha-reductase into 5 alpha-dihydroprogesterone (5 alpha-DHPROG). This enzyme exhibited a 5-fold higher activity in OL than in OPP and OP. 5 alpha-DHPROG was further transformed either into 3 alpha,5 alpha-Tetrahydroprogesterone (3 alpha,5 alpha-THPROG), known as a positive allosteric modulator of the GABA(A) receptor, or into the 3 beta-isomer. The 3 alpha,5 alpha-THPROG synthesis was 10 times higher in OPP than in the other cell studied, while the 3 beta,5 alpha-THPROG production did not change with cell differentiation. PROG synthesis and metabolism and the dramatic changes in neurosteroidogenesis observed during the oligodendroglial differentiation may contribute to oligodendrocyte development or the myelination process.
Roberto Cosimo Melcangi - One of the best experts on this subject based on the ideXlab platform.
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Steroidogenic machinery in the adult rat colon
'Elsevier BV', 2020Co-Authors: S. Diviccaro, S. Giatti, F. Borgo, E. Falvo, D. Caruso, L.m. Garcia-segura, Roberto Cosimo MelcangiAbstract:Gastrointestinal function is known to be regulated by steroid molecules produced by the gonads, the adrenal glands and the gut microbiota. However, we have a limited knowledge on the functional significance of local steroid production by gastrointestinal tract tissue. On this basis, we have here evaluated, as a first methodological approach, the expression of steroidogenic molecules and the local levels of key steroids in the male rat colon. Our findings indicate that the colon tissue expresses molecules involved in the early steps of steroidogenesis and in the consecutive synthesis and metabolism of steroid hormones, such as progesterone, testosterone and 17\u3b2-estradiol. In addition, the levels of the steroid hormone precursor pregnenolone and the levels of active metabolites of progesterone and testosterone, such as dihydroprogesterone, Tetrahydroprogesterone, dihydrotestosterone and 17\u3b2-estradiol, were higher in colon than in plasma. Higher levels of the androgen metabolite 3\u3b1-diol were detected in the colon in comparison with another non-classical steroidogenic tissue, such as the cerebral cortex. These findings suggest the existence of local steroid synthesis and metabolism in the colon, with the production of active steroid metabolites that may impact on the activity of the enteric nervous system and on the composition of the gut microbiota
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patients treated for male pattern hair with finasteride show after discontinuation of the drug altered levels of neuroactive steroids in cerebrospinal fluid and plasma
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Donatella Caruso, Guido Cavaletti, Federico Abbiati, Silvia Giatti, Simone Romano, Letizia Fusco, Roberto Cosimo MelcangiAbstract:Abstract Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandem mass spectrometry, the levels of several neuroactive steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in CSF showed a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and Tetrahydroprogesterone (THP), associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase of T as well as of 3α-diol was detected. Changes in neuroactive steroid levels also occurred in plasma. An increase of PREG, T, 3α-diol, 3β-diol and 17β-estradiol was associated with decreased levels of DHP and THP. The present observations show that altered levels of neuroactive steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment. This article is part of a Special Issue entitled ‘Sex steroids and brain disorders’.
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neuroactive steroid levels are modified in cerebrospinal fluid and plasma of post finasteride patients showing persistent sexual side effects and anxious depressive symptomatology
The Journal of Sexual Medicine, 2013Co-Authors: Roberto Cosimo Melcangi, Donatella Caruso, Federico Abbiati, Silvia Giatti, Donato Calabrese, Fabrizio Piazza, Guido CavalettiAbstract:Abstract Introduction Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α‐reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. Aim A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of neuroactive steroids. Therefore, neuroactive steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long‐term sexual side effects as well as anxious/depressive symptomatology. Methods The levels of neuroactive steroids were evaluated by liquid chromatography–tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. Main Outcome Measures Neuroactive steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. Results At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their neuroactive steroid levels with those of healthy controls. Indeed, decreased levels of Tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17β‐estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5α‐androstane‐3α,17β‐diol and 17β‐estradiol were observed in plasma. Conclusion The present observations confirm that an impairment of neuroactive steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, and Cavaletti G. Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med 2013;10:2598–2603.
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progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy a multimodal analysis
Neuroscience, 2007Co-Authors: E Leonelli, Donatella Crippa, Donatella Caruso, Ilaria Roglio, Giuseppe Lauria, Roberto Bianchi, Luis M Garciasegura, Guido Cavaletti, Valerio Magnaghi, Roberto Cosimo MelcangiAbstract:One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or Tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na+,K+-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na+,K+-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.
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progesterone and its derivatives dihydroprogesterone and Tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats
Neurobiology of Aging, 2003Co-Authors: Inigo Azcoitia, E Leonelli, Luis M Garciasegura, Valerio Magnaghi, Sergio Veiga, Roberto Cosimo MelcangiAbstract:Previous studies indicate that steroid hormones may be protective for Schwann cells and promote the expression of myelin proteins in the sciatic nerve of adult rats. In this study, we have evaluated the effect of progesterone (P), dihydroprogesterone (DHP), Tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT) and 5α-androstan-3α, 17β-diol (3α-diol) on the morphological alterations of myelinated fibers in the sciatic nerve of 22–24-month-old male rats. The sciatic nerves of untreated old male rats, showed a general disorganization and a significant reduction in the density of myelinated fibers, compared to nerves from 3-month-old male rats. The effect of aging was particularly evident in myelinated fibers of small caliber (<5 μm in diameter). In addition, the sciatic nerves of old rats showed a significant increase in the number of fibers with myelin infoldings in the axoplasm and in the number of fibers with irregular shapes. Treatments of old rats with P, DHP and THP resulted in a significant increase in the number of myelinated fibers of small caliber, a significant reduction in the frequency of myelin abnormalities and a significant increase in the g ratio of small myelinated fibers. Furthermore, P treatment significantly reduced the frequency of myelinated fibers with irregular shapes. In contrast, treatments with T, DHT or 3α-diol did not significantly affect any of the morphological parameters examined. In conclusion, our data indicate that P, and its derivatives DHP and THP, are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. These data suggest that P, DHP and THP may represent useful therapeutic alternatives to maintain peripheral nerve integrity in aged animals.
Etienneemile Baulieu - One of the best experts on this subject based on the ideXlab platform.
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progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum
Journal of Neurochemistry, 2003Co-Authors: Abdel M Ghoumari, Bernard Eychenne, Etienneemile Baulieu, Martine Eletr, C Ibanez, Philippe Leclerc, B W Omalley, Michael SchumacherAbstract:We have previously shown that progesterone (PROG) is synthesized by Schwann cells and promotes myelin formation in the peripheral nervous system (PNS). We now report that this neurosteroid also stimulates myelination in organotypic slice cultures of 7-day-old (P7) rat and mouse cerebellum. Myelination was evaluated by immunofluorescence analysis of the myelin basic protein (MBP). After 7 days in culture (7DIV), we found that adding PROG (2–5 × 10−5 M) to the culture medium caused a fourfold increase in MBP expression when compared to control slices. The effect of PROG on MBP expression involves the classical intracellular PROG receptor (PR): the selective PR agonist R5020 significantly increased MBP expression and the PR antagonist mifepristone (RU486) completely abolished the effect of PROG on this MBP expression. Moreover, treatment of P7-cerebellar slice cultures from PR knockout (PRKO) mice with PROG had no significant effect on MBP expression. PROG was metabolized in the cerebellar slices to 5α-dihydroprogesterone (5α-DHP) and to the GABAA receptor-active metabolite 3α,5α-Tetrahydroprogesterone (3α,5α-THP, allopregnanolone). The 5α-reductase inhibitor L685-273 partially inhibited the effect of PROG, and 3α,5α-THP (2–5 × 10−5 M) significantly stimulated the MBP expression, although to a lesser extent than PROG. The increase in MBP expression by 3α,5α-THP involved GABAA receptors, as it could be inhibited by the selective GABAA receptor antagonist bicuculline. These findings suggest that progestins stimulate MBP expression and consequently suggest an increase in CNS myelination via two signalling systems, the intracellular PR and membrane GABAA receptors, and they confirm a new role of GABAA receptors in myelination.
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progesterone and the oligodendroglial lineage stage dependent biosynthesis and metabolism
Glia, 2001Co-Authors: Etienneemile Baulieu, Yvette Akwa, Nathalie Gago, Martine Eletr, N Sananes, Rachida Guennoun, Michael SchumacherAbstract:Evidence has been accumulated showing that neurosteroids, particularly progesterone (PROG) and its metabolites, may participate in myelination and remyelination in the peripheral nervous system, but very few studies have been undertaken in the central nervous system (CNS). The aim of this work was to investigate the capacities of synthesis and metabolism of PROG at three important stages of the oligodendroglial lineage: oligodendrocyte pre-progenitors (OPP), oligodendrocyte progenitors (OP), and fully differentiated oligodendrocytes (OL). Experiments have been conducted in vitro using highly purified primary cell cultures from rat brain. Cells were incubated with (3)H-pregnenolone ((3)H-PREG), the immediate precursor of PROG, or with (3)H-PROG, and steroids metabolites were then identified by thin layer chromatography and high-performance liquid chromatography (HPLC). mRNA expression of key steroidogenic enzymes was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that only OPP and OP, but not OL, expressed 3 beta-hydroxysteroid dehydrogenase/Delta 5-Delta 4 isomerase mRNA and were able to synthesize PROG from PREG. In the three cell types studied, PROG was metabolized by the type 1 isoform of 5 alpha-reductase into 5 alpha-dihydroprogesterone (5 alpha-DHPROG). This enzyme exhibited a 5-fold higher activity in OL than in OPP and OP. 5 alpha-DHPROG was further transformed either into 3 alpha,5 alpha-Tetrahydroprogesterone (3 alpha,5 alpha-THPROG), known as a positive allosteric modulator of the GABA(A) receptor, or into the 3 beta-isomer. The 3 alpha,5 alpha-THPROG synthesis was 10 times higher in OPP than in the other cell studied, while the 3 beta,5 alpha-THPROG production did not change with cell differentiation. PROG synthesis and metabolism and the dramatic changes in neurosteroidogenesis observed during the oligodendroglial differentiation may contribute to oligodendrocyte development or the myelination process.
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progesterone as a neuroactive neurosteroid with special reference to the effect of progesterone on myelination
Steroids, 2000Co-Authors: Etienneemile Baulieu, Michael SchumacherAbstract:Some steroids are synthesized within the central and peripheral nervous system, mostly by glial cells. These are known as neurosteroids. In the brain, certain neurosteroids have been shown to act directly on membrane receptors for neurotransmitters. For example, progesterone inhibits the neuronal nicotinic acetylcholine receptor, whereas its 3alpha,5alpha-reduced metabolite 3alpha, 5alpha-Tetrahydroprogesterone (allopregnanolone) activates the type A gamma-aminobutyric acid receptor complex. Besides these effects, neurosteroids also regulate important glial functions, such as the synthesis of myelin proteins. Thus, in cultures of glial cells prepared from neonatal rat brain, progesterone increases the number of oligodendrocytes expressing the myelin basic protein (MBP) and the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). An important role for neurosteroids in myelin repair has been demonstrated in the rodent sciatic nerve, where progesterone and its direct precursor pregnenolone are synthesized by Schwann cells. After cryolesion of the male mouse sciatic nerve, blocking the local synthesis or action of progesterone impairs remyelination of the regenerating axons, whereas administration of progesterone to the lesion site promotes the formation of new myelin sheaths.
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progesterone as a neuroactive neurosteroid with special reference to the effect of progesterone on myelination
Human Reproduction, 2000Co-Authors: Etienneemile Baulieu, Michael SchumacherAbstract:Some steroids are synthesized within the central and peripheral nervous system, mostly by glial cells. These are known as neurosteroids. In the brain, certain neurosteroids have been shown to act directly on membrane receptors for neurotransmitters. For example, progesterone inhibits the neuronal nicotinic acetylcholine receptor, whereas its 3 a,5a-reduced metabolite 3a,5a-Tetrahydroprogesterone (allopregnanolone) activates the type A g-aminobutyric acid receptor complex. Besides these effects, neurosteroids also regulate important glial functions, such as the synthesis of myelin proteins. Thus, in cultures of glial cells prepared from neonatal rat brain, progesterone increases the number of oligodendrocytes expressing the myelin basic protein (MBP) and the 29,39-cyclic nucleotide-39-phosphodiesterase (CNPase). An important role for neurosteroids in myelin repair has been demonstrated in the rodent sciatic nerve, where progesterone and its direct precursor pregnenolone are synthesized by Schwann cells. After cryolesion of the male mouse sciatic nerve, blocking the local synthesis or action of progesterone impairs remyelination of the regenerating axons, whereas administration of progesterone to the lesion site promotes the formation of new myelin sheaths. © 2000 Published by Elsevier Science Inc.
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validation of an analytical procedure to measure trace amounts of neurosteroids in brain tissue by gas chromatography mass spectrometry
Journal of Chromatography B: Biomedical Sciences and Applications, 2000Co-Authors: Philippe Liere, Antoine Pianos, Bernard Eychenne, Michael Schumacher, Yvette Akwa, Sebastien Weillengerer, Paul Robel, Jan Sjovall, Etienneemile BaulieuAbstract:Abstract A selective and extremely sensitive procedure has been developed and optimized, using high-performance liquid chromatography (HPLC), specific derivatization and gas chromatography–mass spectrometry (GC–MS), to simultaneously quantify very small amounts of different neurosteroids from rat brain. Unconjugated and sulfated steroids in brain extracts were separated by solid-phase extraction. The unconjugated fraction was further purified by HPLC, the steroids being collected in a single fraction, and the sulfated fraction was solvolyzed. All steroids were derivatized with heptafluorobutyric acid anhydride and analyzed by GC–MS (electron impact ionization) using selected-ion monitoring. High sensitivity and accuracy were obtained for all steroids. The detection limits were 1 pg for pregnenolone (PREG), dehydroepiandrosterone (DHEA) and their sulfate esters PREG-S and DHEA-S, 2 pg for progesterone (PROG) and 5 pg for 3α,5α-Tetrahydroprogesterone (3α,5α-THP). In a pilot study on a rat brain, the concentrations of PREG-S and DHEA-S were 8.26±0.80 and 2.47±0.27 ng/g, respectively. Those of PREG, DHEA and PROG were 4.17±0.22, 0.45±0.02 and 1.95±0.10 ng/g, respectively. Good linearity and accuracy were observed for each steroid. The methodology validated here, allows femtomoles of neurosteroids, including the sulfates, found in small brain samples (at least equal to 10 mg) to be quantified simultaneously.
Luis M Garciasegura - One of the best experts on this subject based on the ideXlab platform.
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effects of progesterone and its reduced metabolites dihydroprogesterone and Tetrahydroprogesterone on the expression and phosphorylation of glycogen synthase kinase 3 and the microtubule associated protein tau in the rat cerebellum
Developmental Neurobiology, 2007Co-Authors: Christian Guerraaraiza, Miguel A R Amorim, Ignacio Camachoarroyo, Luis M GarciaseguraAbstract:Progesterone exerts a variety of actions in the brain, where it is rapidly metabolized to 5alpha-dihydroprogesterone (DHP) and 3alpha,5alpha-Tetrahydroprogesterone (THP). The effect of progesterone and its metabolites on the expression and phosphorylation of the microtubule-associated protein Tau and glycogen synthase kinase 3beta (GSK3beta), a kinase involved in Tau phosphorylation, were assessed in two progesterone-sensitive brain areas: the hypothalamus and the cerebellum. Administration of progesterone, DHP, and THP to ovariectomized rats did not affect Tau and GSK3beta assessed in whole hypothalamic homogenates. In contrast, progesterone and its metabolites resulted in a significant decrease in the expression of Tau and GSK3beta in the cerebellum. Furthermore, progesterone administration resulted in an increase in the phosphorylation of two epitopes of Tau (Tau-1 and PHF-1) phosphorylated by GSK3beta, but did not affect the phosphorylation of an epitope of Tau (Ser262) that is GSK3beta insensitive. These effects were accompanied by a decrease in the phosphorylation of GSK3beta in serine, which is associated to an increase in its activity, suggesting that the effect of progesterone on Tau-1 and PHF-1 phosphorylation in the cerebellum is mediated by GSK3beta. The regulation of Tau expression and phosphorylation by progesterone may contribute to the hormonal regulation of cerebellar function by the modification of neuronal cytoskeleton.
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progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy a multimodal analysis
Neuroscience, 2007Co-Authors: E Leonelli, Donatella Crippa, Donatella Caruso, Ilaria Roglio, Giuseppe Lauria, Roberto Bianchi, Luis M Garciasegura, Guido Cavaletti, Valerio Magnaghi, Roberto Cosimo MelcangiAbstract:One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or Tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na+,K+-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na+,K+-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.
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reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo
Journal of Neuroendocrinology, 2004Co-Authors: Iratxe Ciriza, Inigo Azcoitia, Luis M GarciaseguraAbstract:The ovarian hormone progesterone is neuroprotective in some animal models of neurodegeneration. Progesterone actions in the brain may partly be mediated by the locally produced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone. The neuroprotective effects of these two metabolites of progesterone were assessed in this study. Ovariectomized Wistar rats were injected with kainic acid, to induce excitotoxic neuronal death in the hippocampus, and with different doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone. The number of surviving neurones in the hilus of the dentate gyrus of the hippocampus was assessed with the optical disector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurones and in the induction of vimentin expression in reactive astrocytes, a sign of neural damage. Low doses of 5alpha-dihydroprogesterone (0.25 and 0.5 mg/kg body weight, b.w.) prevented the loss of hilar neurones and the appearance of vimentin immunoreactivity in astrocytes. Higher doses (1-2 mg/kg b.w.) were not neuroprotective. By contrast, low doses of 3alpha,5alpha-Tetrahydroprogesterone (0.25-1 mg/kg b.w.) were unable to protect the hilus from kainic acid while higher doses (2-4 mg/kg b.w.) were protective. The different optimal neuroprotective doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone suggest that these two steroids may protect neurones using different mechanisms. The neuroprotective effects of 3alpha,5alpha-Tetrahydroprogesterone may be exerted by the inhibition of neuronal activity via the GABAA receptor. This latter possibility is supported by the observation that 3beta,5alpha-Tetrahydroprogesterone, an isomer of 3alpha,5alpha-Tetrahydroprogesterone that does not bind to GABAA receptor, was not neuroprotective. In summary, our findings suggest that progesterone neuroprotective effects may be, at least in part, mediated by its reduced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone.
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progesterone and its derivatives dihydroprogesterone and Tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats
Neurobiology of Aging, 2003Co-Authors: Inigo Azcoitia, E Leonelli, Luis M Garciasegura, Valerio Magnaghi, Sergio Veiga, Roberto Cosimo MelcangiAbstract:Previous studies indicate that steroid hormones may be protective for Schwann cells and promote the expression of myelin proteins in the sciatic nerve of adult rats. In this study, we have evaluated the effect of progesterone (P), dihydroprogesterone (DHP), Tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT) and 5α-androstan-3α, 17β-diol (3α-diol) on the morphological alterations of myelinated fibers in the sciatic nerve of 22–24-month-old male rats. The sciatic nerves of untreated old male rats, showed a general disorganization and a significant reduction in the density of myelinated fibers, compared to nerves from 3-month-old male rats. The effect of aging was particularly evident in myelinated fibers of small caliber (<5 μm in diameter). In addition, the sciatic nerves of old rats showed a significant increase in the number of fibers with myelin infoldings in the axoplasm and in the number of fibers with irregular shapes. Treatments of old rats with P, DHP and THP resulted in a significant increase in the number of myelinated fibers of small caliber, a significant reduction in the frequency of myelin abnormalities and a significant increase in the g ratio of small myelinated fibers. Furthermore, P treatment significantly reduced the frequency of myelinated fibers with irregular shapes. In contrast, treatments with T, DHT or 3α-diol did not significantly affect any of the morphological parameters examined. In conclusion, our data indicate that P, and its derivatives DHP and THP, are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. These data suggest that P, DHP and THP may represent useful therapeutic alternatives to maintain peripheral nerve integrity in aged animals.
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reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo
Journal of Neuroendocrinology, 2004Co-Authors: Iratxe Ciriza, Inigo Azcoitia, Luis M GarciaseguraAbstract:The ovarian hormone progesterone is neuroprotective in some animal models of neurodegeneration. Progesterone actions in the brain may partly be mediated by the locally produced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone. The neuroprotective effects of these two metabolites of progesterone were assessed in this study. Ovariectomized Wistar rats were injected with kainic acid, to induce excitotoxic neuronal death in the hippocampus, and with different doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone. The number of surviving neurones in the hilus of the dentate gyrus of the hippocampus was assessed with the optical disector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurones and in the induction of vimentin expression in reactive astrocytes, a sign of neural damage. Low doses of 5alpha-dihydroprogesterone (0.25 and 0.5 mg/kg body weight, b.w.) prevented the loss of hilar neurones and the appearance of vimentin immunoreactivity in astrocytes. Higher doses (1-2 mg/kg b.w.) were not neuroprotective. By contrast, low doses of 3alpha,5alpha-Tetrahydroprogesterone (0.25-1 mg/kg b.w.) were unable to protect the hilus from kainic acid while higher doses (2-4 mg/kg b.w.) were protective. The different optimal neuroprotective doses of 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone suggest that these two steroids may protect neurones using different mechanisms. The neuroprotective effects of 3alpha,5alpha-Tetrahydroprogesterone may be exerted by the inhibition of neuronal activity via the GABAA receptor. This latter possibility is supported by the observation that 3beta,5alpha-Tetrahydroprogesterone, an isomer of 3alpha,5alpha-Tetrahydroprogesterone that does not bind to GABAA receptor, was not neuroprotective. In summary, our findings suggest that progesterone neuroprotective effects may be, at least in part, mediated by its reduced metabolites 5alpha-dihydroprogesterone and 3alpha,5alpha-Tetrahydroprogesterone.
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progesterone and its derivatives dihydroprogesterone and Tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats
Neurobiology of Aging, 2003Co-Authors: Inigo Azcoitia, E Leonelli, Luis M Garciasegura, Valerio Magnaghi, Sergio Veiga, Roberto Cosimo MelcangiAbstract:Previous studies indicate that steroid hormones may be protective for Schwann cells and promote the expression of myelin proteins in the sciatic nerve of adult rats. In this study, we have evaluated the effect of progesterone (P), dihydroprogesterone (DHP), Tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT) and 5α-androstan-3α, 17β-diol (3α-diol) on the morphological alterations of myelinated fibers in the sciatic nerve of 22–24-month-old male rats. The sciatic nerves of untreated old male rats, showed a general disorganization and a significant reduction in the density of myelinated fibers, compared to nerves from 3-month-old male rats. The effect of aging was particularly evident in myelinated fibers of small caliber (<5 μm in diameter). In addition, the sciatic nerves of old rats showed a significant increase in the number of fibers with myelin infoldings in the axoplasm and in the number of fibers with irregular shapes. Treatments of old rats with P, DHP and THP resulted in a significant increase in the number of myelinated fibers of small caliber, a significant reduction in the frequency of myelin abnormalities and a significant increase in the g ratio of small myelinated fibers. Furthermore, P treatment significantly reduced the frequency of myelinated fibers with irregular shapes. In contrast, treatments with T, DHT or 3α-diol did not significantly affect any of the morphological parameters examined. In conclusion, our data indicate that P, and its derivatives DHP and THP, are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. These data suggest that P, DHP and THP may represent useful therapeutic alternatives to maintain peripheral nerve integrity in aged animals.