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E E Baulieu

Publications and source records attributed to E E Baulieu.

At least 19 recordsLinked to original sources
PubMed2006

Neuroprotective effect of mifepristone involves neuron depolarization.

In several regions of the developing nervous system, neurons undergo programmed cell death. In the rat cerebellum, Purkinje cell apoptosis is exacerbated when cerebellar slices are cultured during the first postnatal week. To understand the mechanism of this developmental apoptosis, we took advantage of its inhibition by the steroid analog mifepristone. This effect did not involve the classical steroid nuclear receptors. Microarray analysis revealed that mifepristone down-regulated mRNA levels of the Na+/K+-ATPase alpha3 subunit more than three times. Consistent with the down-regulation of the Na+/K+-ATPase, mifepristone caused Purkinje cell membrane depolarization. Depolarizing agents like ouabain (1 microM), tetraethylammonium (2 mM), and veratridine (2 microM) protected Purkinje cells from apoptosis. These results suggest a role of excitatory inputs in Purkinje cell survival during early postnatal development. Indeed, coculturing cerebellar slices with glutamatergic inferior olivary neuron preparations allowed rescue of Purkinje cells. These findings reveal a new neuroprotective mechanism of mifepristone and support a pivotal role for excitatory inputs in the survival of Purkinje neurons. Mifepristone may be a useful lead compound in the development of novel therapeutic approaches for maintaining the resting potential of neurons at values favorable for their survival under neuropathological conditions.

Animals↗
PubMed2005

Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures.

We have previously demonstrated that progesterone significantly increases the rate of myelination in organotypic slice cultures of 7-day-old rat and mouse cerebellum. Here, we show that progesterone (20microM) stimulates the proliferation of oligodendrocyte precursors in cultured cerebellar slices of 7-day-old rats. The steroid increased the number of pre-oligodendrocytes (NG2(+), O4(+)) and to some extent of oligodendrocyte precursors, corresponding to an earlier developmental stage (nestin(+), PDGFalphaR(+), NG2(+), O4(-)). Progesterone stimulated the proliferation of both NG2(+) and O4(+) cells as shown by increased double-immunolabeling with the cell proliferation marker Ki67. The mitogenic effect of progesterone was inhibited by the progesterone receptor antagonist mifepristone (10microM) and could not be mimicked by its GABA-active metabolite 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone), even at the high concentration of 50microM. Results indicate that progesterone first strongly and transiently stimulates the proliferation of oligodendrocyte precursors, and that it may thereafter accelerate their maturation into myelinating oligodendrocytes. Although oligodendrocyte precursors may be a direct target for the actions of progesterone, their number may also be indirectly influenced by the effects of the steroid on neurons and microglial cells, since treatment of the cerebellar slices with progesterone enhanced staining of the neuronal cytoskeleton marker microtubule-associated protein-2 and increased the number of OX-42(+) microglia. A small percentage (about 0.1%) of the NG2(+) cells transiently became OX-42(+) in response to progesterone. These results point to novel mechanisms by which progesterone may promote myelination in the CNS, specifically by stimulating the proliferation and maturation of oligodendrocyte precursors into myelinating oligodendrocytes.

Animals↗
PubMed2003

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system.

Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the beta-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Delta5-androstene-3beta,17beta-diol and to 7alpha-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of beta-amyloid deposits.

Aging↗
PubMed2003

Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum.

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) x 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 5alpha-dihydroprogesterone (5alpha-DHP) and to the GABAA receptor-active metabolite 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP, allopregnanolone). The 5alpha-reductase inhibitor L685-273 partially inhibited the effect of PROG, and 3alpha,5alpha-THP (2(-5) x 10(-5) M) significantly stimulated the MBP expression, although to a lesser extent than PROG. The increase in MBP expression by 3alpha,5alpha-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.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Expression of steroidogenic acute regulatory protein in cultured Schwann cells and its regulation by cAMP.

In steroidogenic cells the steroidogenic acute regulatory (StAR) protein plays a key role in the transport of cholesterol to the inner mitochondrial membrane, where the first step of steroidogenesis, the conversion of cholesterol to pregnenolone, takes place. cAMP is a known positive regulator of StAR gene expression and steroid biosynthesis in steroidogenic cells. As some steroids, such as progesterone, can also be synthesized de novo in the central and peripheral nervous systems and display neuroprotective and neurotrophic effects, we decided to verify the effect of cAMP on StAR gene expression in cultured Schwann cells. We observed that (1) in the presence of serum, forskolin, an agent known to elevate intracellular cAMP, induced both a morphological change and proliferation of cultured Schwann cells; (2) StAR mRNA and protein were expressed in Schwann cells; (3) unexpectedly, forskolin and 8 Br-cAMP, a cell-permeant analogue of cAMP, extinguishcd StAR gene expression; and (4) this response was similar in the presence or absence of serum.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: distinct mechanisms?

The demonstration that the neurosteroid pregnenolone sulfate (PREGS) is active on memory function at both the physiological and pharmacological levels led to us examining in detail the effects of the steroid on spatial working memory by using a two-trial recognition task in a Y-maze, a paradigm based on the natural drive in rodents to explore a novel environment. Dose-response studies in young male adult Sprague-Dawley rats and Swiss mice, after the postacquisition intracerebroventricular injection of steroid, showed an U-inverted curve for memory performance and indicated a greater responsiveness in rats compared with mice. Remarkably, the synthetic (-) enantiomer of PREGS not only also displayed promnesiant activity, but its potency was 10 times higher than that of the natural steroid. Intracerebroventricular coadministration experiments with DL-2-amino-5-phosphonovaleric acid, a competitive selective antagonist of the N-methyl-D-aspartate receptor, abolished the memory-enhancing effect of PREGS, but not that of the PREGS enantiomer, evoking enantiomeric selectivity at the N-methyl-d-aspartate receptor and/or different mechanisms for the promnestic function of the two enantiomers.

2-Amino-5-phosphonovalerate↗
PubMed2001

Prospective measurements of dehydroepiandrosterone sulfate in a cohort of elderly subjects: relationship to gender, subjective health, smoking habits, and 10-year mortality.

The decrease with age of the adrenal-secreted dehydroepiandrosterone sulfate (DHEAS) in serum has suggested that it may be causally related to longevity. For the PAQUID [People (Personnes) Aged (Agées) About What (Quid, in Latin)] cohort of elderly subjects, we have previously reported higher DHEAS in men than in women, a decrease with age and, among men, a negative correlation between the DHEAS level and mortality at 2 and 4 years. Here, with an 8-year followup in 290 subjects, we show a global decrease of 2.3% per year for men and 3.9% per year for women. However, in approximately 30% of cases, there was an increase of DHEAS. We observed no relationship between the evolution of DHEAS level and functional, psychological, and mental status, possibly because of selection by death. In women, no association was found between mortality and DHEAS level. In men, the relative risk (RR) of death was higher for the lowest levels of DHEAS (RR = 1.9, P = 0.007), with RR = 6.5, P = 0.003 for those under 70 years old, a result indicating heterogeneity of the population. There was an effect of subjective health on mortality that disappeared after adjustment of DHEAS levels, suggesting its relation with these DHEAS levels. Death RR was much higher in smokers with a low DHEAS level than in nonsmokers with high DHEAS (RR = 6.7, P = 0.001). We submit that the involvement of DHEAS is possibly different according to gender, that association between low DHEAS level and mortality only for men under 70 years old possibly reflects heterogeneity of the population, and that DHEAS level is a reliable predictor of death in male smokers.

Aged↗
PubMed2001

Progesterone stimulates Krox-20 gene expression in Schwann cells.

The gene of the zinc finger transcription factor Krox-20 (Egr-2) is expressed in Schwann cells and plays an important role in myelination of peripheral nerves. We have shown that progesterone promotes myelination in the regenerating sciatic nerve and in cocultures of Schwann cells and sensory neurones. To determine whether progesterone regulates Krox-20 expression, we measured its effects on Krox-20 mRNA levels in the MSC80 mouse Schwann cell line by semi-quantitative RT-PCR. Although low levels of Krox-20 mRNA are detectable in MSC80 cells cultured in defined medium, treatment with 10(-6) M progesterone induces a rapid (15 min) and transient increase in the levels of Krox-20 mRNA. Lower doses of progesterone (10(-9), 10(-8) and 10(-7) M) are also effective in increasing Krox-20 mRNA. Other steroids including testosterone, dexamethasone, and estradiol are ineffective when added to the culture medium at 10(-6) M for 1 h. The induction of Krox-20 mRNA was also observed with the selective progesterone agonist Organon 2058 and was abolished by treating the MSC80 Schwann cells with the progesterone antagonist RU486, indicating that progesterone induces Krox-20 mRNA expression by binding to its intracellular receptor. The induction of Krox-20 by progesterone was also demonstrated in primary cultures of Schwann cells isolated from neonatal rat sciatic nerves, at the mRNA level by RT-PCR and at the protein level by immunohistochemistry. As Krox-20 is a necessary step for the initiation of myelin formation in peripheral nerves, its stimulation by progesterone suggests an important signalling function for this steroid in myelination.

Animals↗
PubMed2001

Progesterone and the oligodendroglial lineage: stage-dependent biosynthesis and metabolism.

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.

Aging↗
PubMed2001

Neurosteroids: beginning of the story.

Neurosteroids are synthetisized in the central and the peripheral nervous system, in glial cells, and also in neurons, from cholesterol or steroidal precursors imported from peripheral sources. They include 3 beta-hydroxy-delta 5-compounds, such as pregnenolone (PREG) and dehydroepiandrosterone, their sulfate esters, and compounds known as reduced metabolites of steroid hormones, such as the tetrahydroderivative of progesterone 3 alpha-hydroxy-5 alpha-pregnan-20-one. These neurosteroids can act as modulators of neurotransmitter receptors, such as GABAA, NMDA, and sigma 1 receptors. Progesterone itself is also a neurosteroid, and a progesterone receptor has been detected in peripheral and central glial cells. At different sites in the brain, neurosteroid concentrations vary according to environmental and behavioral circumstances, such as stress, sex recognition, or aggressiveness. A physiological function of neurosteroids in the central nervous system is strongly suggested by the role of hippocampal PREGS with respect to memory performance, observed in aging rats. In the peripheral nervous system, a role for PROG synthesized in Schwann cells has been demonstrated in remyelination after cryolesion of the sciatic nerve in vivo and in cultures of dorsal root ganglia. A new mechanism of PREG action discovered in the brain involves specific steroid binding to microtubule associated protein and increased tubulin polymerization for assembling microtubules. It may be important to study the effects of abnormal neurosteroid concentration/metabolism in view of the possible treatment of functional and trophic disturbances of the nervous system.

Animals↗
PubMed2001

Neurosteroids: recent findings.

The term neurosteroid applies to those steroids that are synthesized in the nervous system, from cholesterol or other blood-borne steroidal precursors, and that accumulate in the nervous system to levels that are at least in part independent from steroidogenic gland secretion. Both glial cells and neurons participate in neurosteroid biosynthesis and metabolism. Several neurosteroids are involved in auto/paracrine mechanisms involving regulation of target gene expression and/or effects on membrane receptors (particularly those for neurotransmitters). An additional unexpected mechanism of steroid action is reported here: pregnenolone binds to neural microtubule-associated protein of type 2 (MAP2) and increases both the rate and extent of tubulin polymerization, forming microtubules of normal electron microscopic appearance. This novel mechanism may play a role in regulating microtubule formation and dynamics and thus neuronal plasticity and function.

Animals↗
PubMed2001

Progesterone synthesis and myelin formation in peripheral nerves.

Progesterone is synthesized in the nervous system by neurons and glial cells. Because of their simple structure, plasticity and capacity of regeneration, peripheral nerves are particularly well suited for studying the biosynthesis, mechanisms of action and effects of the hormone. Schwann cells, the myelinating glial cells in the peripheral nervous system, synthesize progesterone in response to a diffusible neuronal signal. In peripheral nerves, the local synthesis of progesterone plays an important role in the formation of myelin sheaths. This has been shown in vivo, after cryolesion of the mouse sciatic nerve, and in vitro, in cocultures of Schwann cells and sensory neurons. Schwann cells also express an intracellular receptor for progesterone, which thus functions as an autocrine signalling molecule. Progesterone may promote myelination by activating the expression of genes coding for transcription factors (Krox-20) and/or for myelin proteins (P0, PMP22). Recently, it has been proposed that progesterone may indirectly regulate myelin formation by influencing gene expression in neurons. Steroid hormones also influence the proliferation of Schwann cells: estradiol becomes a potent mitogen for Schwann cells when levels of cAMP are elevated and glucocorticosteroids have been shown to increase the mitogenic effects of peptide growth factors.

Animals↗
PubMed2001

Synthesis of progesterone in Schwann cells: regulation by sensory neurons.

In peripheral nerves, progesterone synthesized by Schwann cells has been implicated in myelination. In spite of such an important function, little is known of the regulation of progesterone biosynthesis in the nervous system. We show here that in rat Schwann cells, expression of the 3 beta-hydroxysteroid dehydrogenase and formation of progesterone are dependent on neuronal signal. Levels of 3 beta-hydroxysteroid dehydrogenase mRNA and synthesis of [3H]progesterone from [3H]pregnenolone were low in purified Schwann cells prepared from neonatal rat sciatic nerves. However, when Schwann cells were cultured in contact with sensory neurons, both expression and activity of the 3 beta-hydroxysteroid dehydrogenase were induced. Regulation of 3 beta-hydroxysteroid dehydrogenase expression by neurons was also demonstrated in vivo in the rat sciatic nerve. 3 beta-hydroxysteroid dehydrogenase mRNA was present in the intact nerve, but could no longer be detected 3 or 6 days after cryolesion, when axons had degenerated. After 15 days, when Schwann cells made new contact with the regenerating axons, the enzyme was re-expressed. After nerve transection, which does not allow axonal regeneration, 3 beta-hydroxysteroid dehydrogenase mRNA remained undetectable. The regulation of 3 beta-hydroxysteroid dehydrogenase mRNA after lesion was similar to the regulation of myelin protein zero (P0) and peripheral myelin protein 22 (PMP22) mRNAs, supporting an important role of locally formed progesterone in myelination.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Double-blind placebo-controlled trial of oral dehydroepiandrosterone in patients with advanced HIV disease.

OBJECTIVE: Plasma levels of dehydroepiandrosterone sulphate (DHEA-S) decrease with the progression of HIV disease. Here, we report on the efficacy and safety of the oral administration of DHEA as replacement therapy, in patients with advanced HIV disease, in a trial that was primarily aimed at assessing quality of life. DESIGN: The trial was randomized and double-blind. Thirty-two patients were allocated to either DHEA 50 mg per day for 4 months (n = 14) or a matching placebo (n = 18). Clinical data, virological and immunological surrogate markers of HIV infection, plasma levels of DHEA-S and the Medical Outcomes Study HIV Health Survey (MOS-HIV) quality of life scale were recorded every month. RESULTS: The mean age of the patients was 40 +/- 11 years. The mean CD4 cell count at baseline was 32.5 +/- 32.4 x 10(6)/l. The mean DHEA-S plasma level at baseline was 5.23 +/- 0.76 micromol/l. No side-effects related to DHEA occurred during the study. A statistically significant increase in the levels of DHEA-S was observed in the treated group throughout the study (P < 0.01). A significant improvement in the Mental Health and Health Distress dimension of MOS-HIV was observed in the DHEA treated group; P = 0.001 and 0.004, respectively. No change in CD4 cell counts was seen during follow-up. CONCLUSIONS: The administration of DHEA in patients with advanced HIV infection results in improved mental function scores as assessed by the MOS-HIV quality of life scale.

Adult↗
PubMed2001

Vitamin D status and redefining serum parathyroid hormone reference range in the elderly.

Subclinical vitamin D insufficiency is characterized by mild secondary hyperparathyroidism and enhanced risk of osteoporotic fracture. However, although low levels of 25-hydroxyvitamin D (25OHD) are common in otherwise normal elderly people, vitamin D status has not generally been taken into account in the previously published reference values for serum PTH. We measured fasting morning serum (obtained from April through June) PTH, total calcium, albumin, phosphate, creatinine, bone markers, and 25OHD in 280 healthy subjects (140 men and 140 women), aged 60-79 yr. Serum PTH was measured by means of 2 immunoradiometric assays, the Allegro intact PTH assay (Nichols Institute Diagnostics) and the new CAP assay (Scantibodies Laboratory, Inc.). We found a high prevalence (167 of 280; 59.6%) of low 25OHD (< or =30 nmol/L) in these otherwise healthy individuals. The PTH concentrations (95% confidence interval) obtained in the whole group of 280 subjects ranged from 13-64 ng/L for the Allegro assay and from 10-44 ng/L for the CAP assay. In the subjects with a serum 25OHD concentration greater than 30 nmol/L, values for both PTH assays were lower, 10-46 and 9-34 ng/L for the Allegro and the CAP assays, respectively. By using these values as a reference range, approximately 25% of the subjects with a serum 25OHD level of 30 nmol/L or less had a high serum PTH level (whatever the assay), reflecting secondary hyperparathyroidism. This might be missed if the reference PTH values are those obtained in the entire group, as is usually done. These results strongly suggest that vitamin D status should be taken into account when establishing reference values for serum PTH in elderly subjects.

Aged↗