RESUMEN
The 18 kDa translocator protein (TSPO/PBR) is a multifunctional evolutionary highly conserved outer mitochondrial membrane protein. Decades of research has reported an obligatory role of TSPO/PBR in both mitochondrial cholesterol transport and, thus, steroid production. However, the strict dependency of steroidogenesis on TSPO/PBR has remained controversial. The aim of this study was to provide insight into the steroid profile in complete C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout male mice (TSPO-KO) under basal conditions. The steroidome in the brain, adrenal glands, testes and plasma was measured by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). We found that steroids present in wild-type (WT) mice were also detected in TSPO-KO mice, including pregnenolone (PREG), progestogens, mineralo-glucocorticosteroids and androgens. The concentrations of PREG and most metabolites were similar between genotypes, except a significant decrease in the levels of the 5α-reduced metabolites of progesterone (PROG) in adrenal glands and plasma and of the 5α-reduced metabolites of corticosterone (B) in plasma in TSPO-KO compared to WT animals, suggesting other regulatory functions for the TSPO/PBR. The expression levels of the voltage-dependent anion-selective channel (VDAC-1), CYP11A1 and 5α-reductase were not significantly different between both groups. Thus, the complete deletion of the tspo gene in male mice does not impair de novo steroidogenesis in vivo.
Asunto(s)
Receptores de GABA , Espectrometría de Masas en Tándem , Masculino , Ratones , Animales , Receptores de GABA/genética , Receptores de GABA/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Esteroides , Proteínas Portadoras , PregnenolonaRESUMEN
Synapses represent an important target of Alzheimer disease (AD), and alterations of their excitability are among the earliest changes associated with AD development. Synaptic activation has been shown to be protective in models of AD, and deep brain stimulation (DBS), a surgical strategy that modulates neuronal activity to treat neurological and psychiatric disorders, produced positive effects in AD patients. However, the molecular mechanisms underlying the protective role(s) of brain stimulation are still elusive. We have previously demonstrated that induction of synaptic activity exerts protection in mouse models of AD and frontotemporal dementia (FTD) by enhancing the macroautophagy/autophagy flux and lysosomal degradation of pathological MAPT/Tau. We now provide evidence that TFEB (transcription factor EB), a master regulator of lysosomal biogenesis and autophagy, is a key mediator of this cellular response. In cultured primary neurons from FTD-transgenic mice, synaptic stimulation inhibits MTORC1 signaling, thus promoting nuclear translocation of TFEB, which, in turn, induces clearance of MAPT/Tau oligomers. Conversely, synaptic activation fails to promote clearance of toxic MAPT/Tau in neurons expressing constitutively active RRAG GTPases, which sequester TFEB in the cytosol, or upon TFEB depletion. Activation of TFEB is also confirmed in vivo in DBS-stimulated AD mice. We also demonstrate that DBS reduces pathological MAPT/Tau and promotes neuroprotection in Parkinson disease patients with tauopathy. Altogether our findings indicate that stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau. This mechanism, underlying the protective effect of DBS, provides encouraging support for the use of synaptic stimulation as a therapeutic treatment against tauopathies.Abbreviations: 3xTg-AD: triple transgenic AD mice; AD: Alzheimer disease; CSA: cyclosporine A; DBS: deep brain stimulation; DIV: days in vitro; EC: entorhinal cortex; FTD: frontotemporal dementia; gLTP: glycine-induced long-term potentiation; GPi: internal segment of the globus pallidus; PD: Parkinson disease; STN: subthalamic nucleus; TFEB: transcription factor EB.
Asunto(s)
Enfermedad de Alzheimer , Demencia Frontotemporal , Enfermedad de Parkinson , Tauopatías , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Demencia Frontotemporal/metabolismo , Enfermedad de Parkinson/metabolismo , Autofagia , Tauopatías/metabolismo , Ratones Transgénicos , Lisosomas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteínas tau/metabolismoRESUMEN
Translocator protein (TSPO, 18â kDa), formerly known as peripheral benzodiazepine receptor, is an evolutionary well-conserved protein located on the outer mitochondrial membrane. TSPO is involved in a variety of fundamental physiological functions and cellular processes. Its expression levels are regulated under many pathological conditions, therefore, TSPO has been proposed as a tool for diagnostic imaging and an attractive therapeutic drug target in the nervous system. Several synthetic TSPO ligands have thus been explored as agonists and antagonists for innovative treatments as neuroprotective and regenerative agents. In this review, we provide state-of-the-art knowledge of TSPO functions in the brain and peripheral nervous system. Particular emphasis is placed on its contribution to important physiological functions such as mitochondrial homeostasis, energy metabolism and steroidogenesis. We also report how it is involved in neuroinflammation, brain injury and diseases of the nervous system.
Asunto(s)
Proteínas Mitocondriales , Receptores de GABA , Encéfalo/metabolismo , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismoRESUMEN
INTRODUCTION: We previously showed that Nestorone® (NES), a synthetic progestin structurally related to progesterone, stimulated remyelination of the corpus callosum in a Cuprizone (CUP) mouse model of demyelination in intact females by promoting replenishment with mature oligodendrocytes (OL) (Glia. 2015;63:104-117). Here, we further investigated the underlying mechanisms of this promyelinating effect. METHODS: We explored whether NES, applied subcutaneously through Alzet mini-osmotic pumps, regulates specific transcription factors involved in oligodendrocyte progenitor cell (OPC) proliferation and their differentiation into mature OL, using RT-qPCR and Western Blot analysis. RESULTS: Our present data show that in comparison to controls, a one-week treatment with NES, through Alzet mini-osmotic pumps, enhanced the production of three relevant transcription factor mRNAs encoding Olig2, Myt1, and Sox17. After 3 weeks, NES treatment reversed the effect of CUP on the levels of corresponding Olig2, Myt1, and Sox17 proteins. Moreover, in mice receiving NES + Estradiol (E2) co-treatment, levels of Olig2, Myt1, and Sox17 proteins did not change as compared to NES alone. CONCLUSION: NES alone or with E2 increased the levels of transcription factors, essential for myelin synthesis.
Asunto(s)
Enfermedades Desmielinizantes/tratamiento farmacológico , Modelos Animales de Enfermedad , Vaina de Mielina/efectos de los fármacos , Norprogesteronas/uso terapéutico , Remielinización/efectos de los fármacos , Animales , Enfermedades Desmielinizantes/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Norprogesteronas/farmacología , Remielinización/fisiologíaRESUMEN
Alzheimer's disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-ß (Aß) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Esteroides/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Sistema Nervioso/metabolismo , Caracteres Sexuales , Proteínas tau/metabolismoRESUMEN
The treatment of Alzheimer's disease (AD) remains challenging and requires a better in depth understanding of AD progression. Particularly, the link between amyloid protein precursor (APP) processing and Tau pathology development remains poorly understood. Growing evidences suggest that APP processing and amyloid-ß (Aß) release are upstream of Tau pathology but the lack of animal models mimicking the slow progression of human AD raised questions around this mechanism. Here, we described that an AD-like ßAPP processing in adults wild-type rats, yielding to human APP, ßCTF and Aß levels similar to those observed in AD patients, is sufficient to trigger gradual Tauopathy. The Tau hyperphosphorylation begins several months before the formation of both amyloid plaques and tangle-like aggregates in aged rats and without associated inflammation. Based on a longitudinal characterization over 30 months, we showed that extrasynaptic and emotional impairments appear before long-term potentiation deficits and memory decline and so before Aß and Tau aggregations. These compelling data allowed us to (1) experimentally confirm the causal relationship between ßAPP processing and Tau pathology in vivo and without Tau transgene overexpression, (2) support the amyloidogenic cascade and (3) propose a 4-step hypothesis of prodromal AD progression.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Animales , Progresión de la Enfermedad , Femenino , Vectores Genéticos , Humanos , Potenciación a Largo Plazo , Masculino , Fragmentos de Péptidos/metabolismo , Placa Amiloide/metabolismo , Presenilina-1/genética , Agregación Patológica de Proteínas/metabolismo , Ratas WistarRESUMEN
Etifoxine is indicated in humans for treating anxiety. In rodents, besides its anxiolytic-like properties, it has recently shown neuroprotective and neuroregenerative activities. It acts by enhancing GABAA receptor function and by stimulating acute steroid biosynthesis via the activation of the 18-kDa translocator protein. However, the regulatory action of etifoxine on steroid production is not well characterized. In this work, we performed dose-response, acute and chronic time-course experiments on the effects of intraperitoneal injections of etifoxine on steroid levels in adult male rat brain and plasma analyzed by gas chromatography-mass spectrometry. Concentrations of pregnenolone, progesterone and its 5α-reduced metabolites were significantly increased in both tissues in response to 25 and 50mg/kg of etifoxine, as compared with vehicle controls, and reached maximal values at 0.5-1h post-injection. Daily injections of etifoxine (50mg/kg, 15days) kept them increased at day 15. Comparisons between steroidogenic tissues revealed that 1h after 50mg/kg of etifoxine treatment, levels of pregnenolone, progesterone and corticosterone were highest in adrenal glands and markedly increased together with their reduced metabolites. They were also increased by etifoxine in brain and plasma, but not in testis except for corticosterone and its metabolites. In contrast, testosterone level was significantly decreased in testis while with its 5α-reduced metabolites, it was unchanged in brain. Results demonstrate that the modulation of steroid concentrations by etifoxine is dependent on the type of steroid and on the steroidogenic organ. They further suggest that adrenal steroids upregulated by etifoxine make an important contribution to the steroids present in brain. This work provides a precise and complete view of steroids regulated by etifoxine that could be useful in therapeutic research.
Asunto(s)
Proteínas Portadoras/metabolismo , Oxazinas/metabolismo , Oxazinas/farmacocinética , Receptores de GABA-A/metabolismo , Animales , Ansiolíticos/farmacología , Encéfalo/metabolismo , Encéfalo/patología , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Isoquinolinas/farmacología , Ligandos , Masculino , Plasma/metabolismo , Pregnenolona/metabolismo , Progesterona/metabolismo , Ratas , Ratas Sprague-Dawley , Esteroides/metabolismoRESUMEN
RATIONALE: Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Aß and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. OBJECTIVE: The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aß25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. METHODS: B104 cells pretreated with the steroids before Aß25-35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aß25-35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. RESULTS: ent-PREGS and PREGS significantly attenuated the Aß25-35-induced decrease in cell viability. Both steroids prevented the Aß25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aß25-35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aß25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aß25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aß25-35 in contrast to the natural steroids. CONCLUSION: The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/toxicidad , Sulfato de Deshidroepiandrosterona/farmacología , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/toxicidad , Pregnenolona/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Neuritas/efectos de los fármacos , RatasRESUMEN
A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora(+/sg), heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora(+/sg)), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora(+/sg) Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora(+/sg) cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora(+/sg) their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency.
Asunto(s)
Envejecimiento/fisiología , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Cerebelo/metabolismo , Hormonas Esteroides Gonadales/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Células de Purkinje/fisiología , Animales , Castración , Recuento de Células , Cerebelo/citología , Estradiol/sangre , Femenino , Hormonas Esteroides Gonadales/metabolismo , Terapia de Reemplazo de Hormonas , Masculino , Ratones , Ratones Mutantes , Ratones Mutantes Neurológicos , Progesterona/sangre , Células de Purkinje/citología , Testosterona/sangreRESUMEN
This study examined the role of forebrain N-methyl-D-aspartate receptors (NMDA-Rs) in the promnesiant effects of natural (+) pregnenolone sulfate (PREGS) and its synthetic (-) enantiomer ent-PREGS in young adult mice. Using the two-trial arm discrimination task in a Y-maze, PREGS and ent-PREGS administration to control mice increased memory performances. In mice with a knock-out of the NR1 subunit of NMDA-Rs in the forebrain, the promnesiant effect of ent-PREGS was maintained whereas the activity of PREGS was lost. Memory enhancement by PREGS involves the NMDA-R activity in the hippocampal CA1 area and possibly in some locations of the cortical layers, whereas ent-PREGS acts independently of NMDA-R function.
Asunto(s)
Memoria/efectos de los fármacos , Pregnenolona/farmacología , Prosencéfalo/efectos de los fármacos , Esteroides/farmacología , Animales , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Noqueados , N-Metilaspartato/farmacología , Receptores de N-Metil-D-Aspartato/deficiencia , Receptores de N-Metil-D-Aspartato/fisiología , Percepción Espacial/efectos de los fármacos , EstereoisomerismoRESUMEN
Symptomatic medications, l-Dopa and dopaminergic agents, remain the only clinically pertinent pharmacological treatment proven effective and available for the large population of patients with Parkinson's disease. The challenge for the pharmaceutical industry is to develop disease-modifying drugs which could arrest, delay or at least oppose the progression of the specific pathogenic processes underlying Parkinson's disease. The purpose of this review, based on recent biological and genetic data to be validated with appropriate animal models, was to re-examine the putative neuroprotective agents in Parkinson's disease and discuss the development of new strategies with the ultimate goal of demonstrating neurocytoprotective activity in this neurodegenerative disease. Since guidelines for research on neurocytoprotective drugs remain to be written, innovation will be the key to success of future clinical trials. It is reasonable to expect that future advances in our understanding of the pathogenic processes of Parkinson's disease will open the way to new perspectives for the treatment of other neurodegenerative diseases.
Asunto(s)
Antiparkinsonianos/farmacología , Citoprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Citoprotección/fisiología , Modelos Animales de Enfermedad , Humanos , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Pregnenolone sulfate (PREGS) has been shown, either at high nanomolar or at micromolar concentrations, to increase neuronal activity by inhibiting GABAergic and by stimulating glutamatergic neurotransmission. PREGS is also a potent modulator of sigma type 1 (sigma1) receptors. It has been proposed that these actions of PREGS underlie its neuropharmacological effects, and in particular its influence on memory processes. On the other hand, the PREGS-mediated increase in neuronal excitability may become dangerous under particular conditions, for example in the case of excitotoxic stress or convulsions. However, the physiopathological significance of these observations has recently been put into question by the failure to detect significant levels of PREGS within the brain and plasma of rats and mice, either by direct analytical methods based on liquid chromatography/mass spectrometry (LC/MS) or enzyme linked immunosorbent assay (ELISA) with specific antibodies against PREGS, or by indirect gas chromatography/mass spectrometry (GC/MS) analysis with improved sample workup. These recent results have not come to the attention of a large number of neurobiologists interested in steroid sulfates. However, although available direct analytical methods have failed to detect levels of PREGS above 0.1-0.3 ng/g in brain tissue, it may be premature to completely exclude the local formation of biologically active PREGS within specific and limited compartments of the nervous system. In contrast to the situation in rodents, significant levels of sulfated 3beta-hydroxysteroids have been measured in human plasma and brain. Previous indirect measures of steroid sulfates by radioimmunoassays (RIA) or GC/MS had detected elevated levels of PREGS in rodent brain. The discrepancies between the results of different assay procedures have revealed the danger of indirect analysis of steroid sulfates. Indeed, PREGS must be solvolyzed/hydrolyzed prior to RIA or GC/MS analysis, and it is the released, unconjugated PREG which is then quantified. Extreme caution needs to be exercised during the preparation of samples for RIA or GC/MS analysis, because the fraction presumed to contain only steroid sulfates can be contaminated by nonpolar components from which PREG is generated by the solvolysis/hydrolysis/derivatization reactions.
Asunto(s)
Encéfalo/fisiología , Pregnenolona/fisiología , Animales , Barrera Hematoencefálica/fisiología , Química Encefálica , Humanos , Ratones , Pregnenolona/antagonistas & inhibidores , Pregnenolona/metabolismo , Ratas , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/fisiología , Sulfatasas/metabolismo , Sulfotransferasas/metabolismoRESUMEN
The utility and safety of postmenopausal hormone replacement therapy has recently been put into question by large clinical trials. Their outcome has been extensively commented upon, but discussions have mainly been limited to the effects of estrogens. In fact, progestagens are generally only considered with respect to their usefulness in preventing estrogen stimulation of uterine hyperplasia and malignancy. In addition, various risks have been attributed to progestagens and their omission from hormone replacement therapy has been considered, but this may underestimate their potential benefits and therapeutic promises. A major reason for the controversial reputation of progestagens is that they are generally considered as a single class. Moreover, the term progesterone is often used as a generic one for the different types of both natural and synthetic progestagens. This is not appropriate because natural progesterone has properties very distinct from the synthetic progestins. Within the nervous system, the neuroprotective and promyelinating effects of progesterone are promising, not only for preventing but also for reversing age-dependent changes and dysfunctions. There is indeed strong evidence that the aging nervous system remains at least to some extent sensitive to these beneficial effects of progesterone. The actions of progesterone in peripheral target tissues including breast, blood vessels, and bones are less well understood, but there is evidence for the beneficial effects of progesterone. The variety of signaling mechanisms of progesterone offers exciting possibilities for the development of more selective, efficient, and safe progestagens. The recognition that progesterone is synthesized by neurons and glial cells requires a reevaluation of hormonal aging.
Asunto(s)
Terapia de Reemplazo de Estrógeno/métodos , Fenómenos Fisiológicos del Sistema Nervioso , Congéneres de la Progesterona/uso terapéutico , Progesterona/uso terapéutico , Progestinas/uso terapéutico , Envejecimiento/fisiología , Animales , Femenino , Humanos , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Progesterona/farmacología , Congéneres de la Progesterona/farmacología , Progestinas/farmacologíaRESUMEN
According to Evidence-Based-Medicine, any proposal for the rationale treatment of mild cognitive impairment (MCI) must be based on the results of double-blind, randomized clinical trials (RCTs). However, since MCI at the present time does not constitute a homogeneous clinical syndrome, it is still inappropriate to propose a specific drug treatment. Moreover, RCTs assessing the therapeutic value of acetylcholinesterase-inhibitors (AChEIs) are negative either trying to improve symptoms (memory performance) or preventing the conversion from MCI to real Alzheimer's Disease (AD). The same negative results were obtained with drugs targeting some systems considered as the early steps of the pathophysiological cascade leading to dementia: non-steroidal anti-inflammatory compounds (rofecoxib), sex steroid hormones (testosterone, estrogens), or antioxidants (tocopherol). Either MCI is considered as the very early phase of development of AD (and then the treatments will aim at preventively antagonizing the hallmarks of the disease) or MCI is a new entity (and then the drugs will target the associated neurochemical disturbances such as tau protein or soluble Abeta oligomers); MCI could also be considered as a monosymptomatic syndrome (amnesia) leading to the development of pure pro-mnestic drugs. These three hypotheses will be presented on the basis of the neurobiology and the pharmacology, and examples of potentially active candidates will be discussed.
Asunto(s)
Trastornos del Conocimiento/terapia , Anciano , Amnesia/psicología , Amnesia/terapia , Amiloide/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico , Ensayos Clínicos como Asunto , Trastornos del Conocimiento/psicología , Agonistas de Dopamina/farmacología , Hormonas Esteroides Gonadales/sangre , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Dopaminérgicos/efectos de los fármacosRESUMEN
Cognitive psychology has provided clinicians with specific tools for analyzing the processes of cognition (memory, language) and executive functions (attention-concentration, abstract reasoning, planning). Neuropsychology, coupled with the neurosciences (including neuroimaging techniques), has authenticated the existence of early disorders affecting the "superior or intellectual" functions of the human brain. The prevalence of cognitive and attention disorders is high in adults because all the diseases implicating the central nervous system are associated with cognitive correlates of variable intensity depending on the disease process and the age of the patient. In some pathologies, cognitive impairment can be a leading symptom such as in schizophrenia, posttraumatic stress disorder or an emblematic stigmata as in dementia including Alzheimer's disease. Paradoxically, public health authorities have only recognized as medications for improving cognitive symptoms those with proven efficacy in the symptomatic treatment of patients with Alzheimer's disease; the other cognitive impairments are relegated to the orphanage of syndromes and symptoms dispossessed of medication. The purpose of this review is to promote a true "pharmacology of cognition" based on the recent knowledge in neurosciences. Data from adult human beings, mainly concerning memory, language, and attention processes, will be reported. "Drug therapeutic strategies" for improving cognition (except for memory function) are currently rather scarce, but promising perspectives for a new neurobiological approach to cognitive pharmacology will be highlighted.
RESUMEN
Immortalized hypothalamic GT1-7 neurons represent a good model system to investigate the control of GnRH secretion. Using these cells, we observed that the neuroactive steroid, pregnenolone sulfate (PREGS), is able to stimulate the release of GnRH in a dose-dependent manner through N-methyl-D-aspartate (NMDA) receptors, because its action is completely blocked by a specific NMDA receptor antagonist and magnesium. GT1-7 neurons express mRNAs for various mouse NMDA receptor subunits (zeta,1, epsilon3, epsilon4, and epsilon2, corresponding to the NR1, NR2C, NR2D, and NR2B rat subunits) and increase their spontaneous release of GnRH when incubated in the presence of exogenous glutamate or NMDA. In addition, we found that these neurons are able to release and synthesize glutamate, as demonstrated by the presence of glutamate accumulated in the defined incubation medium of the neurons, during the experiment and the expression of mRNA coding for vesicular glutamate transporter 2, a specific marker of glutamatergic neurons. The potentiating effect of PREGS on the secretion of GnRH induced by glutamate is consistent with the role of the steroid as a positive allosteric modulator of NMDA receptors. Together these results point to a novel mechanism by which the neuroactive steroid PREGS may potentiate an autocrine excitatory loop in GnRH neurons.
Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/efectos de los fármacos , Pregnenolona/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Células Cultivadas , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Glicina/metabolismo , Hipotálamo/metabolismo , Ratones , N-Metilaspartato/farmacología , ARN Mensajero/análisis , Receptores AMPA/fisiología , Receptores de GABA-A/fisiología , Receptores de N-Metil-D-Aspartato/genética , Proteína 2 de Transporte Vesicular de Glutamato/genéticaRESUMEN
Neurodegenerative diseases and, in particular, Alzheimer disease, are characterized by progressive neuronal loss correlated in time with the symptoms of the disease considered. Whereas the symptoms of those incapacitating diseases are beginning to be managed with a relative efficacy, the ultimate objective of therapy nonetheless remains preventing cell (neuronal and/or astrocytic) death in a neurocytoprotective approach. In biologic terms, in the light of progress at basic research level, three strategies may be envisaged: (1) antagonizing the cytotoxic causal events (excess intracellular calcium, accumulation of abnormal proteins, excitotoxic effects of amino acids, oxidative stress, processes related to inflammation, etc.); (2) stimulating the endogenous protective processes (anti-free radical or DNA repair systems, production of neurotrophic factors, potential cytoprotective action of steroids, etc.); (3) promoting damaged structure repair strategies (grafts) or deep brain or cortical neurostimulation with a view to triggering (beyond the symptomatic actions) potential 'protective' cell mechanisms. The clinical transition of the various strategies whose efficacy is being tested in animal and/or cell models, experimental analogs of the diseases, and thus the objective demonstration in humans of pharmacological and/or surgical neurocytoprotection, is currently the subject of considerable methodological debate (What are the right psychometric assessment criteria? What are the most pertinent laboratory or neuroradiological markers, etc.?). A number of clinical trials have been completed or are ongoing with drugs that are reputed to be neuroprotective. Thus, elements of the response are beginning to be generated with a view to determining whether it will soon be possible to effectively slow or even stop the neurodegenerative process whose etiology, in most cases, remains obscure.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Apoptosis/efectos de los fármacos , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/fisiología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/prevención & control , Ensayos Clínicos como Asunto , Humanos , Enfermedades Neurodegenerativas/prevención & control , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
The aim of this review is to establish the relationship between treatment with hypnotics and the risk of postural instability and as a consequence, falls and hip fractures, in the elderly. A review of the literature was performed through a search of the MEDLINE, Ingenta and PASCAL databases from 1975 to 2005. We considered as hypnotics only those drugs approved for treating insomnia, i.e. some benzodiazepines and the more recently launched 'Z'-compounds, i.e. zopiclone, zolpidem and zaleplon. Large-scale surveys consistently report increases in the frequency of falls and hip fractures when hypnotics are used in the elderly (2-fold risk). Benzodiazepines are the major class of hypnotics involved in this context; falls and fractures in patients taking Z-compounds are less frequently reported, and in this respect, zolpidem is considered as at risk in only one study. It is important to note, however, that drug adverse effect relationships are difficult to establish with this type of epidemiological data-mining. On the other hand, data obtained in laboratory settings, where confounding factors can be eliminated, prove that benzodiazepines are the most deleterious hypnotics at least in terms of their effects on body sway. Z-compounds are considered safer, probably because of their pharmacokinetic properties as well as their selective pharmacological activities at benzodiazepine-1 (BZ(1)) receptors. The effects of hypnotics on balance, gait and equilibrium are the consequence of differential negative impacts on vigilance and cognitive functions, and are highly dose- and time-dependent. Z-compounds have short half-lives and have less cognitive and residual effects than older medications. Some practical rules need to be followed when prescribing hypnotics in order to prevent falls and hip fractures as much as possible in elderly insomniacs, whether institutionalised or not. These are: (i) establish a clear diagnosis of the sleep disorder; (ii) take into account chronic conditions leading to balance and gait difficulties (motor and cognitive status); (iii) search for concomitant prescription of psychotropics and sedatives; (iv) use half the recommended adult dosage; and (v) declare any adverse effect to pharmacovigilance centres. Comparative pharmacovigilance studies focused on the impact of hypnotics on postural stability are very much needed.
Asunto(s)
Accidentes por Caídas , Benzodiazepinas/uso terapéutico , Fracturas de Cadera , Hipnóticos y Sedantes/uso terapéutico , Equilibrio Postural/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Accidentes por Caídas/economía , Acetamidas/uso terapéutico , Anciano , Anciano de 80 o más Años , Compuestos de Azabiciclo , Benzodiazepinas/efectos adversos , Estudios de Casos y Controles , Fracturas de Cadera/economía , Fracturas de Cadera/etiología , Humanos , Hipnóticos y Sedantes/efectos adversos , Hipnóticos y Sedantes/farmacocinética , Farmacoepidemiología , Piperazinas/uso terapéutico , Postura , Estudios Prospectivos , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Medición de Riesgo , ZolpidemRESUMEN
The peripheral benzodiazepine receptors (PBR) might be involved in certain pathophysiological events, such as anxiety, by stimulating the production of neuroactive steroids in the brain. A recent electrophysiological study has revealed an interaction between PK11195, a PBR ligand and the anxiolytic compound etifoxine at micromolar concentrations. The present work was aimed at further characterizing the etifoxine-PBR interaction. In membrane preparations from intact male rat forebrain, etifoxine uncompetitively inhibited the binding of [(3)H]PK11195 with an IC(50) = 18.3 +/- 1.2 microM, a value consistent with etifoxine plasma and brain concentrations measured after an anxiolytic-like dose (50 mg/kg). In vivo, that etifoxine dose was associated with increased concentrations of pregnenolone, progesterone, 5alpha-dihydroprogesterone and allopregnanolone in plasma and brain of sham-operated animals. In adrenalectomized and castrated rats, etifoxine enhanced the brain levels of these steroids, suggesting a stimulation of their local synthesis and/or a decrease of their disappearance rate, independently of peripheral sources. Finasteride, an inhibitor of 5alpha-reductase that converts progesterone into its 5alpha-reduced metabolites like allopregnanolone, attenuated the anti-conflict effect of etifoxine even though brain allopregnanolone contents were drastically reduced. These results indicate that following activation of the PBR in the brain, an increased cerebral production of allopregnanolone, a potent positive modulator of the GABA(A) receptor function, may partially contribute to the anxiolytic-like effects of etifoxine.
Asunto(s)
Ansiolíticos/farmacología , Encéfalo/efectos de los fármacos , Oxazinas/farmacología , Receptores de GABA-A/efectos de los fármacos , Esteroides/metabolismo , Animales , Encéfalo/metabolismo , Isoquinolinas/metabolismo , Masculino , Pregnanolona/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas WistarRESUMEN
Although dehydroepiandrosterone (DHEA) is widely used in the elderly to prevent some adverse effects of ageing, possible deleterious side effects have not been fully assessed. We evaluated the direct actions of DHEA and DHEA sulphate on angiogenesis, a critical event in pathologies that are common in the elderly (cancer, atherosclerosis, inflammation... etc.). At physiological concentrations found in human plasma following DHEA therapy (1-50 nM), DHEA had no action on angiogenesis in vitro. In contrast, higher concentrations of DHEA (10-100 microM), which can be found in tissues after local administration or storage, inhibited in vitro endothelial cell proliferation (blockage in G2/M), migration and capillary tube formation and in vivo angiogenesis in the Matrigel plug assay. This inhibition might be due to a decreased glucose-6-phosphate dehydrogenase activity and to a modification of the tubulin network involved in cell proliferation and migration. The sulphate ester form of DHEA had no effect on angiogenesis.