Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Mol Psychiatry ; 23(6): 1530-1540, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-28696431

RESUMEN

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Sinapsis/metabolismo , Tauopatías/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Autofagia/fisiología , Encéfalo/metabolismo , Estimulación Encefálica Profunda/métodos , Modelos Animales de Enfermedad , Femenino , Demencia Frontotemporal/metabolismo , Hipocampo/patología , Humanos , Lisosomas/metabolismo , Masculino , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores/metabolismo , Proteínas tau/fisiología
2.
J Steroid Biochem Mol Biol ; 109(1-2): 81-9, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18261897

RESUMEN

Previous work showed that dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary artery hypertension in rat via targeting smooth muscle cells. In our study, DHEA was tested on human pulmonary arterial smooth muscle cells (HPASMC) to identify its mechanism of action under hypoxia in vitro. We show that DHEA decreased HIF-1alpha accumulation under both "chemical hypoxia" with treatment by the iron chelator deferroxamin and gas hypoxia (1% O2). The mRNA levels of HIF-1alpha were unchanged whether or not DHEA was applied under chemical and gas hypoxia, as compared to controls in normoxia, suggesting a post-transcriptional effect of the steroid. Protein levels of prolyl hydroxylases responsible for HIF-1alpha degradation were not modified by DHEA treatment. In addition, a synthetic derivative of DHEA, 3beta-methyl-Delta5-androsten-17-one (which cannot be metabolized), was as active as DHEA on HIF-1alpha accumulation, as well as testosterone and 17beta-estradiol (E2). In HPASMC cultures under normoxia and both types of hypoxia, DHEA gave rise to Delta5-androstene-3beta,17beta-diol (ADIOL) and DHEA-sulfate (DHEA-S). Neither testosterone, nor E2 were found. In addition, ADIOL, DHEA-S, 7alpha-hydroxy-DHEA and Delta4-androstene-3,17-dione were ineffective on HIF-1alpha accumulation. The effect of DHEA per se reducing HIF-1alpha accumulation may be relevant to reduced hypoxia effects in pulmonary arterial hypertension.


Asunto(s)
Deshidroepiandrosterona/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Aminoácidos Dicarboxílicos/farmacología , Secuencia de Bases , Células Cultivadas , Cobalto/farmacología , Cartilla de ADN/genética , Deferoxamina/farmacología , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/metabolismo , Inhibidores Enzimáticos/farmacología , Estradiol/farmacología , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/genética , Hipoxia/complicaciones , Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Quelantes del Hierro/farmacología , Modelos Cardiovasculares , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Procolágeno-Prolina Dioxigenasa/antagonistas & inhibidores , Procolágeno-Prolina Dioxigenasa/metabolismo , Arteria Pulmonar/citología , Testosterona/farmacología
3.
Prog Neurobiol ; 71(1): 3-29, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-14611864

RESUMEN

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.


Asunto(s)
Envejecimiento/efectos de los fármacos , Hormonas/metabolismo , Hormonas/farmacología , Fenómenos Fisiológicos del Sistema Nervioso , Sistema Nervioso/patología , Animales , Demencia/tratamiento farmacológico , Demencia/prevención & control , Femenino , Hormonas/análisis , Humanos , Masculino
4.
Psychopharmacology (Berl) ; 160(2): 113-21, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11875628

RESUMEN

RATIONALE: Corticotropin-releasing factor (CRF) and urocortin (Ucn) belong to the CRF-related family, share a high degree of structural homology and bind to CRF receptors. However, compared with CRF, Ucn was shown to display either weaker or similar anxiogenic-like effects in vivo. OBJECTIVE: To compare the anxiogenic-like responses of rats injected intracerebroventricularly (ICV) with different doses of either rat/human CRF (r/hCRF) or rat Ucn (rUcn) at different intervals after injection. METHODS: Rats were tested on three validated paradigms of emotional behavior [i.e. elevated plus-maze (EPM), defensive withdrawal (DW) and conflict test (CT)] 5 and 30 min after treatment. RESULTS: In the EPM test only r/hCRF, but not rUcn, produced anxiogenic-like effects at the dose of 1.0 microg, when the peptides were injected 5 min before testing. At 30 min after injection, both peptides caused a significant reduction of open arms exploration, rUcn being effective at 0.01 microg. In the DW test both peptides were equally potent in decreasing the exploratory behavior and increasing the time spent in the chamber at the dose of 1.0 microg when tested 30 min after injection. In the CT both rUcn (0.25-1.0 microg) and r/hCRF (0.75-1.0 microg) decreased significantly the responding in the punished component. However, rUcn reduced food responding also in the unpunished component possibly due to its powerful anorectic activity. CONCLUSIONS: Comparison of anxiogenic-like activities of r/hCRF and rUcn at doses up to 1.0 microg revealed striking differential effects that depended on the time of testing after ICV peptide injection, and on the paradigm of anxiety used. These results suggest that the onset of r/hCRF and rUcn actions related to behavioral responses to anxiety is likely to depend on brain peptide-specific mechanisms including binding properties to CRF-receptors, differential distribution to specific functional brain sites and the distribution and effectiveness of binding-protein interactions.


Asunto(s)
Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Hormona Liberadora de Corticotropina/efectos adversos , Animales , Ansiedad/fisiopatología , Hormona Liberadora de Corticotropina/administración & dosificación , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Factores de Tiempo , Urocortinas
5.
Glia ; 36(3): 295-308, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11746767

RESUMEN

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.


Asunto(s)
Envejecimiento/metabolismo , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Diferenciación Celular/fisiología , Molécula L1 de Adhesión de Célula Nerviosa , Oligodendroglía/metabolismo , Progesterona/biosíntesis , Células Madre/metabolismo , Animales , Animales Recién Nacidos , Astrocitos/citología , Astrocitos/metabolismo , Encéfalo/citología , Linaje de la Célula/fisiología , Células Cultivadas , Ectodisplasinas , Técnica del Anticuerpo Fluorescente , Galactosilceramidas/metabolismo , Gangliósidos/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de la Membrana/metabolismo , Microglía/citología , Microglía/metabolismo , Proteína Básica de Mielina/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Oligodendroglía/citología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Ácidos Siálicos/metabolismo , Células Madre/citología
6.
Proc Natl Acad Sci U S A ; 98(24): 14033-7, 2001 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-11717462

RESUMEN

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.


Asunto(s)
Memoria a Corto Plazo/fisiología , Pregnenolona/metabolismo , 2-Amino-5-fosfonovalerato/administración & dosificación , Animales , Cognición/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Pregnenolona/administración & dosificación , Pregnenolona/fisiología , Ratas , Ratas Sprague-Dawley , Esteroides/metabolismo , Análisis y Desempeño de Tareas
7.
J Chromatogr B Biomed Sci Appl ; 739(2): 301-12, 2000 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-10755374

RESUMEN

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 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-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.


Asunto(s)
Química Encefálica , Cromatografía de Gases y Espectrometría de Masas/métodos , Esteroides/análisis , Animales , Cromatografía Líquida de Alta Presión , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
8.
Peptides ; 21(1): 37-44, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10704717

RESUMEN

Central administration of neuropeptide Y (NPY) produces anxiolytic-like behavioral effects in rat models of anxiety. Because previous evidence has suggested a relationship between NPY and corticotropin-releasing factor (CRF) in the brain, we have focused on the interaction of these neuropeptide systems in emotional responsiveness to stressful stimuli. Intracerebroventricular administration of CRF produced a marked response suppression in an operant incremental shock conflict paradigm. NPY [(1 microg, intracerebroventricularly (i.c.v.)] significantly antagonized the response-suppressing effects of CRF (0.75 microg, i.c.v.) on punished responding in the conflict test at doses that produced little or no behavioral effect when administered alone. Central administration of the CRF antagonist [D-Phe(12), Nle(21,38),C(alpha) MeLeu(37)]CRF (D-Phe CRF(12-41)) alone did not alter punished or unpunished responding in the conflict test. However, pretreatment with the CRF antagonist before a subthreshold dose of NPY (1 microg, i.c.v.) produced a significant potentiation of the release of punished responding relative to NPY alone and untreated controls. NPY also antagonized the "anxiogenic-like" behavioral effects of CRF in the elevated plus maze. These findings support the hypothesis that NPY and CRF may reciprocally modulate an animal's behavioral response to stressful stimuli.


Asunto(s)
Ansiedad/inducido químicamente , Ansiedad/prevención & control , Hormona Liberadora de Corticotropina/farmacología , Neuropéptido Y/farmacología , Animales , Ansiedad/psicología , Conflicto Psicológico , Hormona Liberadora de Corticotropina/administración & dosificación , Hormona Liberadora de Corticotropina/análogos & derivados , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Hormona Liberadora de Corticotropina/fisiología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Neuropéptido Y/administración & dosificación , Neuropéptido Y/fisiología , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Wistar
9.
J Neurocytol ; 29(5-6): 307-26, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11424948

RESUMEN

Steroids influence the activity and plasticity of neurons and glial cells during early development, and they continue to exert trophic and protective effects in the adult nervous system. Steroids are produced by the gonads and adrenal glands and reach the brain, the spinal cord and the peripheral nerves via the bloodstream. However, some of them, named "neurosteroids", can also be synthesized within the nervous system. They include pregnenolone, progesterone, dehydroepiandrosterone and their reduced metabolites and sulfate esters. Little is known concerning the regulation of steroid synthesis in the nervous system, which involves interactions between different cell types. For example, the synthesis of progesterone by Schwann cells in peripheral nerves is regulated by a diffusible neuronal signal. Neurotrophic and neuroprotective effects of steroids have been documented both in cell culture and in vivo. PROG plays an important role in the neurological recovery from traumatic injury of the brain and spinal cord by mechanisms involving protection from excitotoxic cell death, lipid peroxydation and the induction of specific enzymes. After transection of the rat spinal cord, PROG increases the number of nitric oxide synthase expressing astrocytes immediately above and below the lesion. PROG also plays an important role in the formation of new myelin sheaths. This has been shown in the regenerating mouse sciatic nerve after lesion and in cocultures of sensory neurons and Schwann cells. PROG promotes myelination by activating the expression of genes coding for myelin proteins. The modulation of neurostransmitter receptors, in particular the type A gamma-aminobutyric acid, the N-methyl-D-aspartate and the sigma 1 receptors, is involved in the psychopharmacological effects of steroids and allows to explain their anticonvulsant, anxiolytic, antidepressive and sedative effects as well as their influence on memory. Pregnenolone sulfate has been shown to reverse age-related deficits in spatial memory performance and to have protective effects on memory in different models of amnesia.


Asunto(s)
Sistema Nervioso/metabolismo , Esteroides/biosíntesis , Esteroides/metabolismo , Animales , Lesiones Encefálicas/metabolismo , Traumatismos de la Médula Espinal/metabolismo
10.
Behav Brain Res ; 106(1-2): 119-25, 1999 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-10595427

RESUMEN

The neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) possesses clear anxiolytic-like effects. Other neurosteroids namely pregnenolone sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEA-S) influence anxiety-related behavior differently. In the present study, the implication of the amygdala, a key structure in mechanisms of fear and anxiety, was investigated as a potential neural substrate for the effects of neurosteroids on anxiety-like behavior in rat. Animals implanted with bilateral cannulae aimed at the central nucleus of the amygdala (CeA) and infused with neurosteroids, were tested in two animal models of anxiety. Allopregnanolone (8 microg/side) produced a significant increase in responding suppressed by punishment in the conflict test. In the elevated plus maze, allopregnanolone (8 microg/side) induced a significant increase in the time spent and the number of entries in open arms compared with the vehicle-infused controls. No significant changes in punished and unpunished responding of the conflict test were observed with PREG-S (0.001-8 microg/side) and DHEA-S (2-8 microg/side) administered into the CeA or into the lateral ventricle (1-20 microg). The results reveal the lack of activity of PREG-S and DHEA-S in the operant conflict test, but suggest that the central nucleus of the amygdala is a key region involved in the mechanisms underlying the anxiolytic-like action of allopregnanolone.


Asunto(s)
Amígdala del Cerebelo/fisiología , Ansiolíticos/farmacología , Pregnanolona/farmacología , Amígdala del Cerebelo/anatomía & histología , Animales , Ansiolíticos/administración & dosificación , Conflicto Psicológico , Sulfato de Deshidroepiandrosterona/administración & dosificación , Sulfato de Deshidroepiandrosterona/farmacología , Femenino , Inyecciones , Inyecciones Intraventriculares , Ovariectomía , Pregnanolona/administración & dosificación , Pregnenolona/administración & dosificación , Pregnenolona/farmacología , Castigo , Ratas , Ratas Wistar
11.
J Soc Biol ; 193(3): 293-8, 1999.
Artículo en Francés | MEDLINE | ID: mdl-10542960

RESUMEN

The term "neurosteroids" applies to those steroids that are both formed in the nervous system from sterol precursors, and accumulate in the nervous system, at least in part, independently of peripheral steroidogenic glands secretion. Neurosteroids that are active on the central nervous system include, mainly, pregnenolone (PREG), dehydroepiandrosterone (DHEA) and their sulfate esters (PREG-S and DHEA-S), as well as the reduced metabolite of progesterone, 3 alpha,5 alpha-TH PROG also called allopregnanolone. These neuroactive neurosteroids alter neuronal excitability by modulating the activity of several neurotransmitter receptors and thus can influence behavior. PREG-S decreases the sleeping time in rats anesthetized with a barbiturate, which is consistent with its antagonist action on the GABAA receptor (GABAA-R). Allopregnanolone is anxiolytic in rats tested in a conflict paradigm, through an interaction at a site specific for the benzodiazepine (BZ) receptor inverse agonist RO15-4513 and/or at the picrotoxinin site on GABAA-R. The contribution of the amygdala, a key region involved in the control of anxiety, is also demonstrated for the anxiolytic action of allopregnanolone. An anti-agressive effect of DHEA can be observed in castrated male mice who become agressive in the presence of lactating females. This inhibition of agressiveness by DHEA is associated to a selective decrease in the brain of PREG-S, which may, in turn, trigger an increase of endogenous GABAergic tone. Finally, cognitive performances of aged rats tested in the Morris water maze and the Y-maze can be correlated with individual concentrations of PREG-S in the hippocampus, i.e. poor performance in both tasks with low levels of PREG-S. Remarkably, the memory deficits are significantly improved, albeit transiently, by an intra-hippocampal injection of PREG-S in impaired aged rats. Promnesiant PREG-S may then reinforce some neurotransmitter systems that can decline with age. This brief review provides evidence of the pharmacology and physiological correlates of neurosteroids involved in behavioral phenomena. However, neurobiological mechanisms of behavioral effects of neurosteroids await further investigation.


Asunto(s)
Encéfalo/fisiología , Cognición/fisiología , Deshidroepiandrosterona/fisiología , Aprendizaje por Laberinto/fisiología , Pregnenolona/fisiología , Esteroides/fisiología , Animales , Cognición/efectos de los fármacos , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/farmacología , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Pregnenolona/análogos & derivados , Pregnenolona/farmacología , Ratas
12.
Brain Res ; 835(1): 46-61, 1999 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-10448195

RESUMEN

Cytokines belonging to the type I interferon (e.g. interferon-alpha) family are important in the host response to infection and may have complex and broad ranging actions in the central nervous system (CNS) that may be beneficial or harmful. To better understand the impact of the CNS expression of the type I interferons (IFN), transgenic mice were developed that produce IFN-alpha(1) chronically from astrocytes. In two independent transgenic lines with moderate and low levels of astrocyte IFN-alpha mRNA expression respectively, a spectrum of transgene dose- and age-dependent structural and functional neurological alterations are induced. Structural changes include neurodegeneration with loss of cholinergic neurons, gliosis, angiopathy with mononuclear cell cuffing, progressive calcification affecting basal ganglia and cerebellum and the up-regulation of a number of IFN-alpha-regulated genes. At a functional level, in vivo and in vitro electrophysiological studies revealed impaired neuronal function and disturbed synaptic plasticity with pronounced hippocampal hyperexcitability. Severe behavioral alterations were also evident in higher expressor GFAP-IFNalpha mice which developed fatal seizures around 13 weeks of age precluding their further behavioral assessment. Modest impairments in discrimination learning were measured in lower expressor GFAP-IFNalpha mice at various ages (7-42 weeks). The behavioral and electrophysiological findings suggest regional changes in hippocampal excitability which may be linked to abnormal calcium metabolism and loss of cholinergic neurons in the GIFN mice. Thus, these transgenic mice provide a novel animal model in which to further evaluate the mechanisms that underlie the diverse actions of type I interferons in the intact CNS and to link specific structural changes with functional impairments.


Asunto(s)
Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Interferón-alfa/biosíntesis , Enfermedades del Sistema Nervioso/genética , Animales , Conducta Animal/fisiología , Electrofisiología , Proteína Ácida Fibrilar de la Glía/biosíntesis , Proteína Ácida Fibrilar de la Glía/genética , Interferón-alfa/genética , Ratones , Ratones Transgénicos , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología
13.
J Immunol ; 161(9): 5016-26, 1998 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-9794439

RESUMEN

Type I IFNs, which include IFN-alpha, appear to have complex and broad-ranging actions in the central nervous system (CNS) that may result in protection or injury. To better understand these issues, we generated transgenic mice that produce IFN-alpha1 chronically from astrocytes. These glial fibrillary acidic protein-IFN-alpha transgenic mice developed a progressive inflammatory encephalopathy, with marked calcium mineralization, meninoencephalitis, gliosis, and neurodegeneration. Many features of this murine encephalopathy resembled those found in certain human encephalopathies of unknown etiology; these diseases, exemplified by Aicardi-Goutières syndrome and some viral encephalopathies, show increased intrathecal production of IFN-alpha. Our data suggest that IFN-alpha overproduction may be the primary factor initiating these human diseases. Following intracerebral infection with lymphocytic choriomeningitis virus, glial fibrillary acidic protein-IFN-alpha mice had significantly increased survival rates associated with markedly reduced virus titers and immune pathology in the brain but normal peripheral CTL responses. Therefore, the production of IFN-alpha in the CNS can be a two-edged sword that on the one hand confers protection against a lethal viral infection but on the other causes significant injury to the brain. These transgenic mice provide a novel animal model in which to further evaluate the mechanisms that underlie the diverse actions of type I IFNs in the intact CNS.


Asunto(s)
Astrocitos/metabolismo , Interferón-alfa/fisiología , Coriomeningitis Linfocítica/prevención & control , Meningoencefalitis/etiología , Enfermedades Neurodegenerativas/etiología , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Calcinosis/etiología , Regulación de la Expresión Génica , Proteína Ácida Fibrilar de la Glía/biosíntesis , Proteína Ácida Fibrilar de la Glía/genética , Gliosis/etiología , Interferón-alfa/efectos adversos , Interferón-alfa/biosíntesis , Interferón-alfa/genética , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/biosíntesis , Linfocitos T Citotóxicos/inmunología , Transgenes , Carga Viral
14.
Neuroimmunomodulation ; 5(3-4): 126-35, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9730678

RESUMEN

To better understand the actions of cytokines in the mammalian central nervous system (CNS), we have developed transgenic mice in which the expression of various cytokines including interleukin (IL)-3, IL-6, IL-12, interferon-alpha or tumor necrosis factor-alpha was targeted to astrocytes under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic lines displaying low astrocyte expression of the respective cytokine were developed and characterized. The findings indicate that expression of these different cytokines in the intact CNS produces divergent inflammatory responses which are associated with the development of wide-ranging and progressive molecular, cellular and functional CNS impairments. These transgenic mice provide a powerful tool which we are now exploiting further to define novel mechanisms that might underlie the individual cytokine-driven neuroinflammatory responses. To date the results clearly show there are distinct model-associated patterns of cerebral expression of key molecules involved in the inflammatory response including the cellular adhesion molecules, chemokines, major histocompatibility complex molecules and the matrix metalloproteinases. In conclusion, these GFAP-cytokine transgenic mice highlight the potent and diverse array of actions mediated by cytokines when expressed in the CNS and provide a valuable resource to further our knowledge of the mechanisms by which cytokines exert their effects.


Asunto(s)
Enfermedades del Sistema Nervioso Central/inmunología , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Humanos , Ratones
15.
Brain Res ; 790(1-2): 334-8, 1998 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-9593978

RESUMEN

Steroids with the 3alpha-hydroxy-5alpha- or 5beta-reduced configurations of the A ring interact with the gamma-aminobutyric acid (GABA) type A receptor chloride channel complex and potentiate the stimulation of Cl- uptake by GABA agonists. Conversely, the sulfate esters of 3beta-hydroxy-5-ene neurosteroids pregnenolone and dehydroepiandrosterone behave as inhibitory modulators. In the present work, steroid sulfates were tested for their ability to modulate muscimol-induced chloride ion uptake into cortical synaptoneurosomes. 3alpha-Hydroxy-5alpha-pregnan-20-one sulfate and several other 3alpha-hydroxy-steroid sulfates potentiated, whereas 3beta-hydroxy-steroid sulfates inhibited muscimol effect. It is concluded that GABA-agonistic or antagonistic properties of steroid sulfates depend on the alpha or beta orientation of the sulfate moiety linked to the A ring.


Asunto(s)
Cloruros/farmacocinética , Agonistas de Receptores de GABA-A , Receptores de GABA-A/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Sulfato de Deshidroepiandrosterona/farmacología , Agonistas del GABA/farmacología , Moduladores del GABA/farmacología , Técnicas In Vitro , Ionóforos/farmacología , Masculino , Muscimol/farmacología , Pregnanolona/farmacología , Pregnenolona/farmacología , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo
16.
Eur J Pharmacol ; 325(1): 1-7, 1997 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-9151931

RESUMEN

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) was administered systemically to rats which were tested in the Geller-Seifter conflict paradigm, an established animal model of anxiety. Allopregnanolone was found to produce significant anxiolytic-like effects at a dose of 8 mg/kg. When three ligands that function at different sites on the gamma-aminobutyric acid/benzodiazepine receptor-chloride ionophore complex (GABA(A) receptors) were examined in conjunction with allopregnanolone, the anti-conflict effects of allopregnanolone were effectively reversed only by the benzodiazepine receptor inverse agonist RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-alpha]-[1,4]benzodiazepine-3-carboxylate). Since this inverse agonist has been reported to inhibit the GABA(A)-activated chloride flux in neuronal membranes, it is likely that the stimulation of the chloride channel in GABA(A) receptors is an important component of the effects of allopregnanolone. In contrast, the benzodiazepine receptor antagonist flumazenil (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) did not block the anxiolytic-like actions of allopregnanolone, indicating that allopregnanolone does not bind at the benzodiazepine site directly. Isopropylbicyclophosphate, which binds at the picrotoxinin site on the GABA(A) receptors and blocks the behavioral actions of ethanol, also dose-dependently reversed the anti-conflict effect of this neurosteroid. The results suggest that allopregnanolone may be working either at a site specific for the benzodiazepine receptor inverse agonist RO15-4513 or at the picrotoxinin site to produce its potent anxiolytic-like behavioral effects.


Asunto(s)
Ansiolíticos/farmacología , Pregnanolona/farmacología , Receptores de GABA-A/efectos de los fármacos , Marcadores de Afinidad/farmacología , Animales , Ansiedad/tratamiento farmacológico , Azidas/farmacología , Conducta Animal/efectos de los fármacos , Benzodiazepinas/farmacología , Sitios de Unión , Canales de Cloruro/antagonistas & inhibidores , Conflicto Psicológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Flumazenil/farmacología , Moduladores del GABA/farmacología , Agonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-A , Compuestos Organofosforados/farmacología , Ratas , Ratas Wistar
17.
Biochem J ; 322 ( Pt 1): 175-84, 1997 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-9078259

RESUMEN

The metabolism of 27-, 25- and 24-hydroxycholesterol in cultures of rat astrocytes, Schwann cells and neurons was studied. 27- and 25-Hydroxycholesterol, but not 24-hydroxycholesterol, underwent 7 alpha-hydroxylation with subsequent oxidation to 7 alpha-hydroxy-3-oxo-delta 4 steroids in all three cell types. When cells were incubated for 24 h with 0.28 nmol of 27-hydroxycholesterol in 10 ml of medium, the rates of conversion into 7 alpha-hydroxylated metabolites were 0.21, 0.12 and 0.02 nmol/24 h per 10(6) cells in the media of astrocytes, Schwann cells and neurons respectively. The corresponding values for 25-hydroxycholesterol were 0.26, 0.16 and 0.04. A minor fraction of 27-hydroxycholesterol and its 7 alpha-hydroxylated metabolites was oxidized to 3 beta-hydroxy-5-cholestenoic acid. 3 beta, 7 alpha-dihydroxy-5-cholestenoic acid and 7 alpha-hydroxy-3-oxo-4-cholestenoic acid. In addition to the two hydroxycholesterols, other 3 beta-hydroxy-delta 4 steroids, dehydro-epiandrosterone, pregnenolone, 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid underwent 7 alpha-hydroxylation. Competitive experiments did not distinguish between the presence of one or several 7 alpha-hydroxylases. In astrocyte incubations, 27-hydroxycholesterol also underwent 25-hydroxylation, and 12% of its metabolites carried a 25-hydroxy group. 25-Hydroxylation of added 24-hydroxycholesterol was also observed in the astrocyte incubations, as was the formation of 7 alpha, 25-dihydroxy-4-cholesten-3-one, 25-hydroxycholesterol and 7 alpha, 25-dihydroxycholesterol from endogenous precursor(s). Our study indicates that side-chain oxygenated cholesterol can undergo metabolic transformations that may be of importance for cholesterol homoeostasis in the brain.


Asunto(s)
Hidroxicolesteroles/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Animales , Astrocitos/metabolismo , Encéfalo/metabolismo , Células Cultivadas , Colestenonas/análisis , Colesterol/análogos & derivados , Colesterol/metabolismo , Ácidos Cólicos/metabolismo , Feto , Hidroxilación , Microsomas/metabolismo , Ratas , Ratas Sprague-Dawley , Células de Schwann/metabolismo , Especificidad por Sustrato
18.
Eur J Neurosci ; 9(11): 2236-47, 1997 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9464919

RESUMEN

Steroids which are synthesized within the nervous system, such as progesterone, have been termed 'neurosteroids'. Levels of progesterone are much larger in peripheral nerves of rats and mice than in plasma, and persist after removal of the steroidogenic endocrine glands. Schwann cells are a source of progesterone: when isolated from embryonic dorsal root ganglia, they can synthesize progesterone from pregnenolone, the obligate precursor of all steroids. Locally produced progesterone has been shown to play an important role in myelination of peripheral nerve. We show here that sensory neurons from embryonic dorsal root ganglia also express 3beta-hydroxysteroid dehydrogenase and can convert [3H]pregnenolone to [3H]progesterone. Moreover, when cultured under different conditions and incubated for 24 h in the presence of 100 nM [3H]pregnenolone, they produce 5-10 times more [3H]progesterone than Schwann cells. The conversion of pregnenolone to progesterone by neurons is further increased by a diffusible factor produced by Schwann cells. Sensory neurons can also metabolize progesterone to 5alpha-dihydroprogesterone, but unlike Schwann cells, they do not produce 3alpha,5alpha-tetrahydroprogesterone, a potent positive allosteric modulator of gamma-aminobutyric acid type A receptors. We also show that cells isolated from the adult nervous system still have the capacity to convert [3H]pregnenolone to progesterone and its 5alpha-reduced metabolites: neurons and Schwann cells purified from dorsal root ganglia of 6 week old male rats show a similar pattern of pregnenolone metabolism to cells isolated from 18 day old embryos. These findings further support the important role of progesterone in the development and regeneration of the peripheral nervous system.


Asunto(s)
3-Hidroxiesteroide Deshidrogenasas/biosíntesis , Neuronas Aferentes/enzimología , Células de Schwann/enzimología , Esteroides/fisiología , Animales , Southern Blotting , Células Cultivadas , Femenino , Ganglios Espinales/citología , Ganglios Espinales/enzimología , Inmunohistoquímica , Hibridación in Situ , Masculino , Reacción en Cadena de la Polimerasa , Embarazo , Pregnenolona/metabolismo , Progesterona/metabolismo , Ratas , Ratas Sprague-Dawley
19.
Cell Mol Neurobiol ; 16(2): 143-54, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8743966

RESUMEN

1. Some progesterone is synthesized within both the central and the peripheral nervous systems, where it regulates neurotransmission and important glial functions, such as the formation of myelin. Progesterone can thus be designated a "neurosteroid." 2. Steroids act not only on the brain, but also on peripheral nerves, which offer many advantages to study the biological significance of locally produced neurosteroids: their remarkable plasticity and regenerative capacity and their relatively simple structure. 3. By using the regenerating mouse sciatic nerve as a model, we have shown that progesterone synthesized by rat Schwann cells promotes the formation of new myelin sheaths. Progesterone also increases the number of myelinated axons when added at a low concentration to cocultures of Schwann cells and sensory neurons. 4. These findings show a function on myelination for locally produced progesterone and suggest a new pharmacological approach of myelin repair.


Asunto(s)
Sistema Nervioso Central/fisiología , Sistema Nervioso Periférico/fisiología , Progesterona/fisiología , Animales , Sistema Nervioso Central/química , Sistema Nervioso Periférico/química , Esteroides/fisiología , Transmisión Sináptica/efectos de los fármacos
20.
Science ; 268(5216): 1500-3, 1995 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-7770777

RESUMEN

Progesterone is shown here to be produced from pregnenolone by Schwann cells in peripheral nerves. After cryolesion of the sciatic nerve in male mice, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impaired remyelination. Administration of progesterone or its precursor, pregnenolone, to the lesion site increased the extent of myelin sheath formation. Myelination of axons was also increased when progesterone was added to cultures of rat dorsal root ganglia. These observations indicate a role for locally produced progesterone in myelination, demonstrate that progesterone is not simply a sex steroid, and suggest a new therapeutic approach to promote myelin repair.


Asunto(s)
Vaina de Mielina/fisiología , Progesterona/biosíntesis , Células de Schwann/metabolismo , Animales , Axones/ultraestructura , Células Cultivadas , Dihidrotestosterona/análogos & derivados , Dihidrotestosterona/farmacología , Ganglios Espinales , Masculino , Ratones , Mifepristona/farmacología , Vaina de Mielina/ultraestructura , Regeneración Nerviosa , Pregnenolona/metabolismo , Pregnenolona/farmacología , Progesterona/farmacología , Progesterona/fisiología , Nervio Ciático/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA