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1.
J Neuroendocrinol ; 30(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28650095

RESUMO

Steroids are neuroprotective and a growing body of evidence indicates that mitochondria are a potential target of their effects. The mitochondria are the site of cellular energy synthesis, regulate oxidative stress and play a key role in cell death after brain injury and neurodegenerative diseases. After providing a summary of the literature on the general functions of mitochondria and the effects of sex steroid administrations on mitochondrial metabolism, we summarise and discuss our recent findings concerning sex differences in brain mitochondrial function under physiological and pathological conditions. To analyse the influence of endogenous sex steroids, the oxidative phosphorylation system, mitochondrial oxidative stress and brain steroid levels were compared between male and female mice, either intact or gonadectomised. The results obtained show that females have higher a mitochondrial respiration and lower oxidative stress compared to males and also that these differences were suppressed by ovariectomy but not orchidectomy. We have also shown that the decrease in brain mitochondrial respiration induced by ischaemia/reperfusion is different according to sex. In both sexes, treatment with progesterone reduced the ischaemia/reperfusion-induced mitochondrial alterations. Our findings indicate sex differences in brain mitochondrial function under physiological conditions, as well as after stroke, and identify mitochondria as a target of the neuroprotective properties of progesterone. Thus, it is necessary to investigate sex specificity in brain physiopathological mechanisms, especially when mitochondria impairment is involved.


Assuntos
Encéfalo/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Caracteres Sexuais , Acidente Vascular Cerebral/metabolismo , Animais , Feminino , Masculino , Camundongos , Fosforilação Oxidativa , Consumo de Oxigênio/fisiologia
2.
J Neuroendocrinol ; 30(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28675779

RESUMO

Progesterone shows anti-inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Because neurosteroids have been implicated as protective factors for MS and EAE, we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR) and aromatase, whereas changes of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were not significant. mRNA translocator protein (18 kDa) (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNAs. Progesterone pretreatment before EAE induction increased Star, VDAC, P450scc, 5α-reductase type I, 3α-HSOR and aromatase mRNAs and did not modify 3ß-HSD. TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNAs. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3ß-HSD, 3α-HSOR and 5α-reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS. The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti-inflammatory effects of exogenous progesterone given to EAE mice.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Neurotransmissores/biossíntese , Progesterona/uso terapêutico , Animais , Encefalomielite Autoimune Experimental/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia
3.
Neuroscience ; 308: 51-63, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26349009

RESUMO

Wobbler mutant mice suffer from progressive motoneuron degeneration and glial cell reactivity in the spinal cord. To prevent development of these abnormalities, we employed Nestorone, a high-affinity progesterone receptor agonist endowed with neuroprotective, promyelinating and anti-inflammatory activities in experimental brain ischemia, preventing neuroinflammation and chemical degeneration. Five-month-old Wobbler mice (wr-/wr-) received s.c. injections of 200µg/day/mouse of Nestorone in vegetable oil or vehicle for 10days. Control NFR/NFR mice (background strain for Wobbler) received vehicle only. Vehicle-treated Wobblers showed typical spinal cord abnormalities, such as vacuolated motoneurons, decreased immunoreactive choline-acetyltransferase, decreased expression of glutamine synthase (GS), increased glial fibrillary acidic protein-positive (GFAP) astrogliosis and curved digits in forelimbs. These cell-specific abnormalities were normalized in Nestorone-treated Wobblers. In addition, vehicle-treated Wobblers showed Iba1+ microgliosis, high expression of the microglial marker CD11b mRNA and up-regulation of the proinflammatory markers TNFα and iNOS mRNAs. In Nestorone-treated Wobblers, Iba1+ microgliosis subsided, whereas CD11b, TNFα and iNOS mRNAs were down-regulated. NFκB mRNA was increased in Wobbler spinal cord and decreased by Nestorone, whereas expression of its inhibitor IκBα was increased in Nestorone-treated Wobblers compared to control mice and vehicle-treated Wobblers. In conclusion, our results showed that Nestorone restraining effects on proinflammatory mediators, microgliosis and astrogliosis may support neurons in their resistance against degenerative processes.


Assuntos
Anti-Inflamatórios/farmacologia , Doença dos Neurônios Motores/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Norprogesteronas/farmacologia , Receptores de Progesterona/agonistas , Medula Espinal/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Modelos Animais de Doenças , Gliose/tratamento farmacológico , Gliose/patologia , Gliose/fisiopatologia , Masculino , Camundongos Mutantes , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/fisiopatologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Receptores de Progesterona/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Resultado do Tratamento
4.
J Steroid Biochem Mol Biol ; 146: 48-61, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25196185

RESUMO

Progesterone is a well-known steroid hormone, synthesized by ovaries and placenta in females, and by adrenal glands in both males and females. Several tissues are targets of progesterone and the nervous system is a major one. Progesterone is also locally synthesized by the nervous system and qualifies, therefore, as a neurosteroid. In addition, the nervous system has the capacity to bio-convert progesterone into its active metabolite allopregnanolone. The enzymes required for progesterone and allopregnanolone synthesis are widely distributed in brain and spinal cord. Increased local biosynthesis of pregnenolone, progesterone and 5α-dihydroprogesterone may be a part of an endogenous neuroprotective mechanism in response to nervous system injuries. Progesterone and allopregnanolone neuroprotective effects have been widely recognized. Multiple receptors or associated proteins may contribute to the progesterone effects: classical nuclear receptors (PR), membrane progesterone receptor component 1 (PGRMC1), membrane progesterone receptors (mPR), and γ-aminobutyric acid type A (GABAA) receptors after conversion to allopregnanolone. In this review, we will succinctly describe progesterone and allopregnanolone biosynthetic pathways and enzyme distribution in brain and spinal cord. Then, we will summarize our work on progesterone receptor distribution and cellular expression in brain and spinal cord; neurosteroid stimulation after nervous system injuries (spinal cord injury, traumatic brain injury, and stroke); and on progesterone and allopregnanolone neuroprotective effects in different experimental models including stroke and spinal cord injury. We will discuss in detail the neuroprotective effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABAA receptors.


Assuntos
Lesões Encefálicas/metabolismo , Sistema Nervoso Central/metabolismo , Fármacos Neuroprotetores/farmacologia , Pregnanolona/metabolismo , Progesterona/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Doenças Neurodegenerativas/metabolismo , Pregnanolona/farmacologia , Progesterona/farmacologia , Receptores de GABA-A/metabolismo , Receptores de Progesterona/metabolismo , Medula Espinal
5.
Prog Neurobiol ; 113: 6-39, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24172649

RESUMO

Progesterone is commonly considered as a female reproductive hormone and is well-known for its role in pregnancy. It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system. Progesterone and allopregnanolone are associated with adaptation to stress, and increased production of progesterone within the brain may be part of the response of neural cells to injury. Progesterone receptors (PR) are widely distributed throughout the brain, but their study has been mainly limited to the hypothalamus and reproductive functions, and the extra-hypothalamic receptors have been neglected. This lack of information about brain functions of PR is unexpected, as the protective and trophic effects of progesterone are much investigated, and as the therapeutic potential of progesterone as a neuroprotective and promyelinating agent is currently being assessed in clinical trials. The little attention devoted to the brain functions of PR may relate to the widely accepted assumption that non-reproductive actions of progesterone may be mainly mediated by allopregnanolone, which does not bind to PR, but acts as a potent positive modulator of γ-aminobutyric acid type A (GABA(A) receptors. The aim of this review is to critically discuss effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABA(A) receptors, with main focus on the brain.


Assuntos
Encéfalo/metabolismo , Pregnanolona/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Animais , Feminino , Humanos , Masculino , Proto-Oncogene Mas
6.
J Neuroendocrinol ; 25(11): 1095-103, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23639063

RESUMO

Progesterone is a neuroprotective, promyelinating and anti-inflammatory factor for the nervous system. Here, we review the effects of progesterone in models of motoneurone degeneration and neuroinflammation. In neurodegeneration of the Wobbler mouse, a subset of spinal cord motoneurones showed increased activity of nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of respiratory chain complexes, and decreased activity and protein expression of Mn-superoxide dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several degrees of motor impairment. Progesterone treatment restored the expression of neuronal markers, decreased the activity of NOS and enhanced complex I respiratory activity and MnSOD2. Long-term treatment with progesterone increased muscle strength, biceps weight and survival. Collectively, these data suggest that progesterone prevented neurodegeneration. To study the effects of progesterone in neuroinflammation, we employed mice with experimental autoimmune encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of the inflammatory mediators tumour necrosis factor (TNF)α and its receptor TNFR1, the microglial marker CD11b, inducible NOS and the toll-like receptor 4. Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells became targets of progesterone anti-inflammatory effects. These results represent a starting point for testing the usefulness of neuroactive steroids in neurological disorders.


Assuntos
Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Progestinas/farmacologia , Animais , Camundongos
7.
J Neuroendocrinol ; 25(3): 235-43, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23157231

RESUMO

It is now recognised that progesterone plays a protective role for diseases of the central nervous system. In the Wobbler mouse, a model of motoneurone degeneration, progesterone treatment prevents spinal cord neuropathology and clinical progression of the disease. However, neuropathological and functional abnormalities have also been discovered in the brain of Wobbler mice and patients with amyotrophic lateral sclerosis. The present study examined the hippocampus of control and afflicted Wobbler mice and the changes in response to progesterone treatment. Mice received either a single progesterone implant (20 mg for 18 days). We found that the hippocampal pathology of the untreated Wobblers involved a decreased expression of brain-derived neurotrophic factor (BDNF) mRNA, decreased astrogliosis in the stratum lucidum, stratum radiatum and stratum lacunosum-moleculare, decreased doublecortin (DCX)-positive neuroblasts in the subgranular zone of the dentate gyrus and a decreased density of GABA immunoreactive hippocampal interneurones and granule cells of the dentate gyrus. Although progesterone did not change the normal parameters of control mice, it attenuated several hippocampal abnormalities in Wobblers. Thus, progesterone increased hippocampal BDNF mRNA expression, decreased glial fibrillary acidic protein-positive astrocytes and increased the number of GABAergic interneurones and granule cells. The number of DCX expressing neuroblasts and immature neurones remained impaired in both progesterone-treated and untreated Wobblers. In conclusion, progesterone treatment exerted beneficial effects on some aspects of hippocampal neuropathology, suggesting its neuroprotective role in the brain, in agreement with previous data obtained in the spinal cord of Wobbler mice.


Assuntos
Hipocampo/efeitos dos fármacos , Progesterona/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Duplacortina , Feminino , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/anormalidades , Hipocampo/metabolismo , Hibridização In Situ , Masculino , Camundongos , RNA Mensageiro/genética
8.
Neuroscience ; 231: 111-24, 2013 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-23211561

RESUMO

Progesterone has been shown to exert pleiotropic actions in the brain of both male and females. In particular, after traumatic brain injury (TBI), progesterone has important neuroprotective effects. In addition to intracellular progesterone receptors, membrane receptors of the hormone such as membrane progesterone receptor (mPR) may also be involved in neuroprotection. Three mPR subtypes (mPRα, mPRß, and mPRγ) have been described and mPRα is best characterized pharmacologically. In the present study we investigated the distribution, cellular localization and the regulation of mPRα in male mouse and rat brain. We showed by reverse transcription-PCR that mPRα is expressed at similar levels in the male and female mouse brain suggesting that its expression may not be influenced by steroid levels. Treatment of males by estradiol or progesterone did not modify the level of expression of mPRα as shown by Western blot analysis. In situ hybridization and immunohistochemistry analysis showed a wide expression of mPRα in particular in the olfactory bulb, striatum, cortex, thalamus, hypothalamus, septum, hippocampus and cerebellum. Double immunofluorescence and confocal microscopy analysis showed that mPRα is expressed by neurons but not by oligodendrocytes and astrocytes. In the rat brain, the distribution of mPRα was similar to that observed in mouse brain; and after TBI, mPRα expression was induced in oligodendrocytes, astrocytes and reactive microglia. The wide neuroanatomical distribution of mPRα suggests that this receptor may play a role beyond neuroendocrine and reproductive functions. However, in the absence of injury its role might be restricted to neurons. The induction of mPRα after TBI in microglia, astrocytes and oligodendrocytes, points to a potential role in mediating the modulatory effects of progesterone in inflammation, ion and water homeostasis and myelin repair in the injured brain.


Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Membrana Celular/metabolismo , Receptores de Progesterona/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Lesões Encefálicas/genética , Membrana Celular/efeitos dos fármacos , Membrana Celular/genética , Estradiol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/lesões , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/genética
9.
Neuroscience ; 201: 267-79, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22123169

RESUMO

Previous results have shown a depletion of brain-derived neurotrophic factor (BDNF) mRNA in the degenerating motoneurons from clinically afflicted Wobbler mice, whereas progesterone treatment reverts this depletion. We now compared progesterone regulation of BDNF in motoneurons and oligodendrocytes of Wobbler mice at the progressive (EP, 1-3 months), symptomatic (SYM, 5-8 months old), and late stages (LS, 12-13 months). As controls we used NFR/NFR mice. Controls and Wobbler mice of different ages remained untreated or received a 20 mg progesterone pellet during 18 days. BDNF mRNA was determined in the ventral, intermediolateral, and dorsal gray matter by film autoradiography and in motoneurons using in situ hybridization. A depletion of BDNF mRNA already occurred at the EP stage of Wobblers, but progesterone was inactive at this period. In contrast, progesterone upregulated the low levels of BDNF mRNA in SYM Wobblers in the three gray matter regions analyzed. Progesterone also increased BDNF mRNA in LS Wobblers, according to grain counting procedures. BDNF protein analyzed by enzyme-linked immunosorbent assay (ELISA) in ventral horns or immunostaining of motoneurons was normal in steroid-naive SYM Wobblers. BDNF protein was decreased by progesterone, suggesting increased anterograde transport and/or release of neuronal BDNF. Wobbler mice also showed depletion of CC1-immunopositive oligodendrocytes, whereas progesterone treatment enhanced the density of BDNF+ and CC1+ oligodendrocytes in EP, SYM, and LS Wobblers. Our results suggest that BDNF could be involved in progesterone effects on motoneurons at the SYM and LS periods, whereas effects on oligodendrocytes occurred at all stages of the Wobbler disease. These steroid actions may be important to arrest the ongoing neurodegeneration.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Progesterona/administração & dosagem , Fatores Etários , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Mutantes Neurológicos , Doença dos Neurônios Motores/tratamento farmacológico , Doença dos Neurônios Motores/genética , Mutação , Neuroglia/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/genética
10.
Horm Mol Biol Clin Investig ; 7(3): 403-11, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25961276

RESUMO

Far beyond its role in reproduction, progesterone exerts neuro-protective, promyelinating, and anti-inflammatory effects in the nervous system. These effects are amplified under pathological conditions, implying that changes of the local environment sensitize nervous tissues to steroid therapy. The present survey covers our results of progesterone neuroprotection in a motoneuron neurodegeneration model and a neuroinflammation model. In the degenerating spinal cord of the Wobbler mouse, progesterone reverses the impaired expression of neurotrophins, increases enzymes of neurotransmission and metabolism, prevents oxidative damage of motoneurons and their vacuolar degeneration (paraptosis), and attenuates the development of mitochondrial abnormalities. After long-term treatment, progesterone also increases muscle strength and the survival of Wobbler mice. Subsequently, this review describes the effects of progesterone in mice with induced experimental autoimmune encephalomyelitis (EAE), a commonly used model of multiple sclerosis. In EAE mice, progesterone attenuates the clinical severity, decreases demyelination and neuronal dysfunction, increases axonal counts, reduces the formation of amyloid precursor protein profiles, and decreases the aberrant expression of growth-associated proteins. These actions of progesterone may be due to multiple mechanisms, considering that classic nuclear receptors, extranuclear receptors, and membrane receptors are all expressed in the spinal cord. Although many aspects of progesterone action in humans remain unsolved, data provided by experimental models makes getting to this objective closer than previously expected.

11.
Neuroscience ; 166(1): 94-106, 2010 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-20025939

RESUMO

The recent molecular cloning of membrane receptors for progesterone (mPRs) has tremendous implications for understanding the multiple actions of the hormone in the nervous system. The three isoforms which have been cloned from several species, mPRalpha, mPRbeta and mPRgamma, have seven-transmembrane domains, are G protein-coupled and may thus account for the rapid modulation of many intracellular signaling cascades by progesterone. However, in order to elucidate the precise functions of mPRs within the nervous system it is first necessary to determine their expression patterns and also to develop new pharmacological and molecular tools. The aim of the present study was to profile mPR expression in the mouse spinal cord, where progesterone has been shown to exert pleiotropic actions on neurons and glial cells, and where the hormone can also be locally synthesized. Our results show a wide distribution of mPRalpha, which is expressed in most neurons, astrocytes, oligodendrocytes, and also in a large proportion of NG2(+) progenitor cells. This mPR isoform is thus likely to play a major role in the neuroprotective and promyelinating effects of progesterone. On the contrary, mPRbeta showed a more restricted distribution, and was mainly present in ventral horn motoneurons and in neurites, consistent with an important role in neuronal transmission and plasticity. Interestingly, mPRbeta was not present in glial cells. These observations suggest that the two mPR isoforms mediate distinct and specific functions of progesterone in the spinal cord. A significant observation was their very stable expression, which was similar in both sexes and not influenced by the presence or absence of the classical progesterone receptors. Although mPRgamma mRNA could be detected in spinal cord tissue by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization analysis did not allow us to verify and to map its presence, probably due to its relatively low expression. The present study is the first precise map of the regional and cellular distribution of mPR expression in the nervous system, a prior requirement for in vivo molecular and pharmacological strategies aimed to elucidate their precise functions. It thus represents a first important step towards a new understanding of progesterone actions in the nervous system within a precise neuroanatomical context.


Assuntos
Membrana Celular/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/genética , Medula Espinal/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Membrana Celular/genética , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Neuroglia/citologia , Neurônios/citologia , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Reação em Cadeia da Polimerase , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptores de Progesterona/metabolismo , Medula Espinal/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo
12.
Brain Res Rev ; 57(2): 493-505, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17618691

RESUMO

Progesterone has neuroprotective effects in the injured and diseased spinal cord and after traumatic brain injury (TBI). In addition to intracellular progesterone receptors (PR), membrane-binding sites of progesterone may be involved in neuroprotection. A first putative membrane receptor of progesterone, distinct from the classical intracellular PR isoforms, with a single membrane-spanning domain, has been cloned from porcine liver. Homologous proteins were cloned in rats (25-Dx), mice (PGRMC1) and humans (Hpr.6). We will refer to this progesterone-binding protein as 25-Dx. The distribution and regulation of 25-Dx in the nervous system may provide some clues to its functions. In spinal cord, 25-Dx is localized in cell membranes of dorsal horn neurons and ependymal cells lining the central canal. A role of 25-Dx in mediating the protective effects of progesterone in the spinal cord is supported by the observation that its mRNA and protein are up-regulated by progesterone in dorsal horn of the injured spinal cord. In contrast, the classical intracellular PRs were down-regulated under these conditions. In brain, 25-Dx is particularly abundant in the hypothalamic area, circumventricular organs, ependymal cells of the ventricular walls, and the meninges. Interestingly, it is co-expressed with vasopressin in neurons of the paraventricular, supraoptic and retrochiasmatic nuclei. In response to TBI, 25-Dx expression is up-regulated in neurons and induced in astrocytes. The expression of 25-Dx in structures involved in cerebrospinal fluid production and osmoregulation, and its up-regulation after brain damage, point to a potentially important role of this progesterone-binding protein in the maintenance of water homeostasis after TBI. Our observations suggest that progesterone's actions may involve different signaling mechanisms depending on the pathophysiological context, and that 25-Dx may be involved in the neuroprotective effect of progesterone in the injured brain and spinal cord.


Assuntos
Lesões Encefálicas/metabolismo , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Encéfalo/metabolismo , Expressão Gênica , Humanos , Medula Espinal/metabolismo , Regulação para Cima
13.
Endocrinology ; 148(5): 2505-17, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17303653

RESUMO

Steroids in brain arise from the peripheral endocrine glands and local synthesis. In traumatic brain injury (TBI), the endogenous circulating hormones at the time of injury are important for neuroprotection. In particular, pseudopregnant females recover better than males from TBI. We investigated the effect of pseudopregnancy and TBI on steroid levels in plasma and in three brain regions (within, adjacent, and distal to the lesion site), 6 and 24 h after prefrontal cortex injury. The following steroids were analyzed by gas chromatography/mass spectrometry: pregnenolone, progesterone, 5alpha-dihydroprogesterone, 3alpha,5alpha-tetrahydroprogesterone, 3beta,5alpha-tetrahydroprogesterone, dehydroepiandrosterone, Delta(4)-androstenedione, testosterone, 5alpha-dihydrotestosterone, 3alpha,5alpha-tetrahydrotestosterone, 3beta,5alpha-tetrahydrotestosterone, and 17beta-estradiol. Corticosterone was assayed in plasma to account for stress in the rats. We found different steroid profiles in brain and plasma of male and pseudopregnant female rats and specific profile changes after TBI. In sham-operated pseudopregnant females, much higher levels of progesterone, 5alpha-dihydroprogesterone, 3alpha,5alpha-tetrahydroprogesterone, and 3beta,5alpha-tetrahydroprogesterone were measured in both brain and plasma, compared with sham-operated males. Plasma levels of corticosterone were high in all groups, indicating that the surgeries induced acute stress. Six hours after TBI, the levels of pregnenolone, progesterone, and 5alpha-dihydroprogesterone increased, and those of testosterone decreased in male brain, whereas levels of 5alpha-dihydroprogesterone and 3beta,5alpha-tetrahydroprogesterone increased in brain of pseudopregnant female rats. Plasma levels of 5alpha-dihydroprogesterone did not change after TBI, suggesting a local activation of the 5alpha-reduction pathway of progesterone in both male and pseudopregnant female brain. The significant increase in neurosteroid levels in the male brain after TBI is consistent with their role in neuroprotection. In pseudopregnant females, high levels of circulating progestagens may provide protection against TBI.


Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Pseudogravidez/metabolismo , Esteroides/sangue , Esteroides/química , Animais , Corticosterona/sangue , Feminino , Masculino , Gravidez , Progestinas/sangue , Progestinas/química , Ratos , Fatores Sexuais
14.
Endocrinology ; 147(4): 1847-59, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16396987

RESUMO

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.


Assuntos
5-alfa-Di-Hidroprogesterona/análise , Pregnanolona/análise , Pregnenolona/análise , Progesterona/análise , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/química , 17-Hidroxiesteroide Desidrogenases/genética , Animais , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Pregnenolona/metabolismo , Progesterona/metabolismo , Progesterona/farmacologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/cirurgia
15.
Ann Endocrinol (Paris) ; 66(4): 347-54, 2005 Sep.
Artigo em Francês | MEDLINE | ID: mdl-16392185

RESUMO

Cystic fibrosis is an autosomal recessive disorder affecting about 1/3500 case in France. The disease, that affects all epithelia, is responsible for pulmonary tract infections but also pancreas, gut, liver and genital tract abnormalities. It is linked to CFTR gene mutations, inducing unusually high increase of sodium chloride in sweat, used to track down the illness. deltaF508 CFTR mutation, encountered in 70% of cases, is nearly always associated to pancreatic insufficiency with early-onset lung attack. Around 10% of cystic fibrosis cases, whatever the age, are complicated with partially insulinopenic diabetes, favored by pancreatic fibrosis, while one third of patients shows glucose intolerance. After 20 years old, one third of patients suffers from diabetes and one half after 30 years. Diabetes diagnosis is difficult, and requires the fulfillment of oral glucose tolerance test (OGTT). One glycemia greater or equal to 2 g/l, two hours after a 75 g glucose load, established diabetes diagnosis. Indeed, fasting blood glucose and glycated hemoglobin appear as poor diagnosis markers. Despite histological arguments in favor of the mainly mechanical islet disturbances, an increased prevalence of anti-islets auto-antibodies and an increased frequency of HLA DR3/DR4 have been reported in cystic fibrosis population with glucose tolerance troubles. Also, glucose metabolism is influenced by specific factors linked to cystic fibrosis (infection, malnutrition, steroids...). In reason of the silent phase of diabetes, systematic tracking down of diabetes with a yearly OGTT is recommended, all the more so that hyperglycemia appears as a worsening factor of cystic fibrosis. The efficacy of oral anti-diabetic drugs has not been evaluated on large studies. By contrast, some studies argue for insulin therapy as soon as diabetes appears, insulin improving respiratory and nutritional prognosis. In conclusion, the aim of treatment of cystic fibrosis is to prevent the lung function decline by controlling inflammation and infection, to implement endo- and exo-crine pancreas insufficiency, and to improve nutritional status.


Assuntos
Fibrose Cística/complicações , Diabetes Mellitus/etiologia , Adulto , Autoanticorpos/sangue , Fibrose Cística/genética , Fibrose Cística/terapia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Fibrose , Genótipo , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Teste de Tolerância a Glucose , Antígeno HLA-DR3/análise , Antígeno HLA-DR4/análise , Humanos , Ilhotas Pancreáticas/imunologia , Mutação , Pâncreas/patologia , Fenótipo
16.
Neuroscience ; 125(3): 605-14, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15099674

RESUMO

Progesterone (PROG) provides neuroprotection to the injured central and peripheral nervous system. These effects may be due to regulation of myelin synthesis in glial cells and also to direct actions on neuronal function. Recent studies point to neurotrophins as possible mediators of hormone action. Here, we show that the expression of brain-derived neurotrophic factor (BDNF) at both the mRNA and protein levels was increased by PROG treatment in ventral horn motoneurons from rats with spinal cord injury (SCI). Semiquantitative in situ hybridization revealed that SCI reduced BDNF mRNA levels by 50% in spinal motoneurons (control: 53.5+/-7.5 grains/mm(2) vs. SCI: 27.5+/-1.2, P<0.05), while PROG administration to injured rats (4 mg/kg/day during 3 days, s.c.) elicited a three-fold increase in grain density (SCI+PROG: 77.8+/-8.3 grains/mm(2), P<0.001 vs. SCI). In addition, PROG enhanced BDNF immunoreactivity in motoneurons of the lesioned spinal cord. Analysis of the frequency distribution of immunoreactive densities (chi(2): 812.73, P<0.0001) showed that 70% of SCI+PROG motoneurons scored as dark stained whereas only 6% of neurons in the SCI group belonged to this density score category (P<0.001). PROG also prevented the lesion-induced chromatolytic degeneration of spinal cord motoneurons as determined by Nissl staining. In the normal intact spinal cord, PROG significantly increased BDNF inmunoreactivity in ventral horn neurons, without changes in mRNA levels. Our findings suggest that PROG enhancement of endogenous neuronal BDNF could provide a trophic environment within the lesioned spinal cord and might be part of the PROG activated-pathways to provide neuroprotection.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neurônios Motores/metabolismo , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Neurônios Motores/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/fisiopatologia , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Progesterona/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
17.
J Neurochem ; 87(4): 902-13, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14622121

RESUMO

Progesterone provides neuroprotection after spinal cord injury, but the molecular mechanisms involved in this effect are not completely understood. In this work, expression of two binding proteins for progesterone was studied in intact and injured rat spinal cord: the classical intracellular progesterone receptor (PR) and 25-Dx, a recently discovered progesterone membrane binding site. RT-PCR was employed to determine their relative mRNA levels, whereas cellular localization and relative protein levels were investigated by immunocytochemistry. We observed that spinal cord PR mRNA was not up-regulated by estrogen in contrast to what is observed in many brain areas and in the uterus, but was abundant as it amounted to a third of that measured in the estradiol-stimulated uterus. In male rats with complete spinal cord transection, levels of PR mRNA were significantly decreased, while those of 25-Dx mRNA remained unchanged with respect to control animals. When spinal cord-injured animals received progesterone treatment during 72 h, PR mRNA levels were not affected and remained low, whereas 25-Dx mRNA levels were significantly increased. Immunostaining of PR showed its intracellular localization in both neurons and glial cells, whereas 25-Dx immunoreactivity was localized to cell membranes of dorsal horn and central canal neurons. As the two binding proteins for progesterone differ with respect to their response to lesion, their regulation by progesterone, their cellular and subcellular localizations, their functions may differ under normal and pathological conditions. These observations point to a novel and potentially important role of the progesterone binding protein 25-Dx after injury of the nervous system and suggest that the neuroprotective effects of progesterone may not necessarily be mediated by the classical progesterone receptor but may involve distinct membrane binding sites.


Assuntos
Proteínas de Transporte/metabolismo , Progesterona/farmacologia , Receptores de Progesterona/metabolismo , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Proteínas de Transporte/genética , Modelos Animais de Doenças , Estradiol/farmacologia , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Proteínas de Membrana , Regeneração Nervosa/fisiologia , Progesterona/sangue , Progesterona/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
18.
J Steroid Biochem Mol Biol ; 85(1): 89-94, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12798361

RESUMO

We have shown that progesterone (PROG) has a stimulatory effect on myelin formation after sciatic nerve injury. PROG is synthesized from pregnenolone (PREG) by the enzyme 3 beta-hydroxysteroid dehydrogenase isomerase (3beta-HSD). At the occasion of the 15th International Symposium of the Journal of the Steroid Biochemistry and Molecular Biology, we presented some of our recent results demonstrating, expression and activity of the enzyme 3beta-HSD in the rat sciatic nerve. We determined the kinetic properties of 3beta-HSD and its regulation by PROG and estradiol. The expression of 3beta-HSD protein was assessed by Western-blot analysis, and the 3beta-HSD activity was evaluated by incubating homogenates with [3H]-PREG as substrate and NAD(+) as cofactor. Levels of steroids formed were calculated either by extrapolation of the relationship between the tritiated peaks obtained by thin layer chromatography (TLC) and the initial amount of PREG, or by gas chromatography-mass spectrometry (GC-MS) determination. A rapid increase in PROG formation was found between 0 and 50min of incubation and no significant change was observed between 1 and 4h. The calculated K(m) value was close to the values obtained for the 3beta-HSD types I and IV isoforms. Trilostane caused a potent inhibition of the rate of conversion of PREG to PROG. When we tested the effects of progesterone and estradiol on 3beta-HSD activity, a significant inhibition was obtained.


Assuntos
Di-Hidrotestosterona/análogos & derivados , Complexos Multienzimáticos/metabolismo , Pregnenolona/metabolismo , Progesterona Redutase/metabolismo , Progesterona/metabolismo , Nervo Isquiático/metabolismo , Esteroide Isomerases/metabolismo , Animais , Western Blotting , Cromatografia em Camada Fina , Di-Hidrotestosterona/farmacologia , Inibidores Enzimáticos/farmacologia , Estradiol , Cromatografia Gasosa-Espectrometria de Massas , Cinética , Masculino , Complexos Multienzimáticos/antagonistas & inibidores , Progesterona Redutase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/enzimologia , Esteroide Isomerases/antagonistas & inibidores
19.
J Neurochem ; 84(1): 119-26, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12485408

RESUMO

In the peripheral nervous system, progesterone (PROG) has a stimulatory effect on myelination. It could be derived from local synthesis, as Schwann cells in culture express the 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and convert pregnenolone (PREG) to PROG. Although 3beta-HSD mRNA can be detected by RT-PCR in peripheral nerves, the activity of the enzyme has so far not been demonstrated and characterized in nerve tissue. In this study, we show that homogenates prepared from rat sciatic nerves contain a functional 3beta-HSD enzyme and we have analysed its kinetic properties and its regulation by steroids. The activity of 3beta-HSD in homogenates was evaluated using 3H-labelled PREG as a substrate and NAD+ as a cofactor, the levels of steroids formed were calculated either by extrapolating the relationship between tritiated peaks obtained by TLC to the initial amount of PREG, or by gas chromatography/mass spectrometry determination. A rapid increase in PROG formation was found between 0 and 50 min of incubation and no further significant changes were observed between 1 and 4 h. The calculated Km value (1.06 +/- 0.19 microm) was close to the values described for the 3beta-HSD type-I and type-IV isoforms. Trilostane, a competitive inhibitor of the 3beta-HSD caused a potent inhibition of the rate of conversion of PREG to PROG (IC50 = 4.06 +/- 2.58 microm). When the effects of different steroids were tested, both oestradiol and PROG significantly inhibited the conversion of PREG to PROG.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Di-Hidrotestosterona/análogos & derivados , Isomerases/metabolismo , Nervo Isquiático/enzimologia , 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Animais , Di-Hidrotestosterona/farmacologia , Inibidores Enzimáticos/farmacologia , Estradiol/farmacologia , Hormônios/farmacologia , Cinética , Masculino , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley
20.
Ann N Y Acad Sci ; 973: 83-7, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12485839

RESUMO

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.


Assuntos
AMP Cíclico/fisiologia , Fosfoproteínas/genética , Células de Schwann/fisiologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Animais Recém-Nascidos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Colforsina/farmacologia , Cinética , Proteínas de Membrana/genética , Ratos , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos
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