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1.
Cell ; 145(6): 863-74, 2011 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-21640374

RESUMEN

Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Huntington/tratamiento farmacológico , Ácido Quinurénico/análisis , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Tiazoles/uso terapéutico , Administración Oral , Enfermedad de Alzheimer/fisiopatología , Animales , Química Encefálica , Modelos Animales de Enfermedad , Femenino , Humanos , Ácido Quinurénico/sangre , Masculino , Ratones , Ratones Transgénicos , Sulfonamidas/administración & dosificación , Tiazoles/administración & dosificación
2.
Bioorg Med Chem Lett ; 59: 128577, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35065232

RESUMEN

The ubiquitously expressed ABL1 and ABL2 protein kinases play many important roles in cell function. Although they have been implicated in neuron development, maintenance and signaling, there are no good tool compounds to evaluate the effects of ABL kinase inhibition in the brain. Asciminib is a recently approved drug that specifically and potently inhibits the tyrosine kinase activity of ABL1, ABL2 and that of the chimeric BCR-ABL1 oncoprotein which causes chronic myeloid leukemia. Herein we show that asciminib does not penetrate the intact blood-brain barrier (BBB) following administration to rats, which curtails its utility for assessing the in vivo effects of ABL kinase inhibition in the brain. However, we describe another specific ABL kinase inhibitor, possessing physicochemical characteristics suitable for BBB penetration, and which after administration (either i.v., i.p. or p.o.) to mice achieves substantial, pharmacologically relevant brain concentrations. This bipyridine compound (4) therefore has potential for elucidating the role of ABL kinases in the brain in non-clinical studies.


Asunto(s)
Antineoplásicos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Niacinamida/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Barrera Hematoencefálica/metabolismo , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Niacinamida/administración & dosificación , Niacinamida/química , Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirazoles/administración & dosificación , Pirazoles/química , Ratas , Relación Estructura-Actividad
3.
Proc Natl Acad Sci U S A ; 115(37): E8765-E8774, 2018 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-30150378

RESUMEN

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Enfermedad de Huntington/fisiopatología , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Neuronas/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Modelos Animales de Enfermedad , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Ventrículos Laterales/patología , Masculino , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Neuronas/fisiología , Panobinostat , Ratas
4.
Hum Mol Genet ; 23(14): 3641-56, 2014 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-24556212

RESUMEN

Ageing is associated with the reduced performance of physiological processes and has been proposed as a major risk factor for disease. An age-related decline in stress response pathways has been widely documented in lower organisms. In particular, the heat shock response (HSR) becomes severely compromised with age in Caenorhabditis elegans. However, a comprehensive analysis of the consequences of ageing on the HSR in higher organisms has not been documented. We used both HS and inhibition of HSP90 to induce the HSR in wild-type mice at 3 and 22 months of age to investigate the extent to which different brain regions, and peripheral tissues can sustain HSF1 activity and HS protein (HSP) expression with age. Using chromatin immunoprecipitation, quantitative reverse transcription polymerase chain reaction, western blotting and enzyme linked immunosorbent assay (ELISA), we were unable to detect a difference in the level or kinetics of HSP expression between young and old mice in all brain regions. In contrast, we did observe an age-related reduction in chaperone levels and HSR-related proteins in the heart. This could result in a decrease in the protein folding capacity of old hearts with implications for age-related cardiac disorders.


Asunto(s)
Envejecimiento/fisiología , Encéfalo/crecimiento & desarrollo , Corazón/crecimiento & desarrollo , Respuesta al Choque Térmico , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Factores de Transcripción del Choque Térmico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Respuesta al Choque Térmico/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Miocardio/patología , Pliegue de Proteína , Piridonas/farmacología , Pirimidinas/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
5.
J Biol Chem ; 289(29): 19894-906, 2014 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-24855652

RESUMEN

The heat shock response, resulting in the production of heat shock proteins or molecular chaperones, is triggered by elevated temperature and a variety of other stressors. Its master regulator is heat shock transcription factor 1 (HSF1). Heat shock factors generally exist in multiple isoforms. The two known isoforms of HSF1 differ in the inclusion (HSF1α) or exclusion (HSF1ß) of exon 11. Although there are some data concerning the differential expression patterns and transcriptional activities of HSF2 isoforms during development, little is known about the distinct properties of the HSF1 isoforms. Here we present evidence for two novel HSF1 isoforms termed HSF1γα and HSF1γß, and we show that the HSF1 isoform ratio differentially regulates heat shock protein gene transcription. Hsf1γ isoforms are expressed in various mouse tissues and are translated into protein. Furthermore, after heat shock, HSF1γ isoforms are exported from the nucleus more rapidly or degraded more quickly than HSF1α or HSF1ß. We also show that each individual HSF1 isoform is sufficient to induce the heat shock response and that expression of combinations of HSF1 isoforms, in particular HSF1α and HSF1ß, results in a synergistic enhancement of the transcriptional response. In addition, HSF1γ isoforms potentially suppress the synergistic effect of HSF1α and HSF1ß co-expression. Collectively, our observations suggest that the expression of HSF1 isoforms in a specific ratio provides an additional layer in the regulation of heat shock protein gene transcription.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas de Choque Térmico/biosíntesis , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/biosíntesis , Chaperonas Moleculares/genética , Factores de Transcripción/metabolismo , Transporte Activo de Núcleo Celular , Secuencia de Aminoácidos , Animales , Línea Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Femenino , Factores de Transcripción del Choque Térmico , Respuesta al Choque Térmico/genética , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Datos de Secuencia Molecular , Isoformas de Proteínas/deficiencia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Homología de Secuencia de Aminoácido , Distribución Tisular , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Transcripción Genética
6.
J Neurosci ; 32(50): 18259-68, 2012 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-23238740

RESUMEN

Peripheral immune cells and brain microglia exhibit an activated phenotype in premanifest Huntington's disease (HD) patients that persists chronically and correlates with clinical measures of neurodegeneration. However, whether activation of the immune system contributes to neurodegeneration in HD, or is a consequence thereof, remains unclear. Signaling through cannabinoid receptor 2 (CB(2)) dampens immune activation. Here, we show that the genetic deletion of CB(2) receptors in a slowly progressing HD mouse model accelerates the onset of motor deficits and increases their severity. Treatment of mice with a CB(2) receptor agonist extends life span and suppresses motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB(2) receptor antagonist blocks these effects. CB(2) receptors regulate blood interleukin-6 (IL-6) levels, and IL-6 neutralizing antibodies partially rescue motor deficits and weight loss in HD mice. These findings support a causal link between CB(2) receptor signaling in peripheral immune cells and the onset and severity of neurodegeneration in HD, and they provide a novel therapeutic approach to treat HD.


Asunto(s)
Enfermedad de Huntington/inmunología , Enfermedad de Huntington/metabolismo , Leucocitos/metabolismo , Receptor Cannabinoide CB2/metabolismo , Transducción de Señal/fisiología , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Enfermedad de Huntington/patología , Interleucina-6/inmunología , Interleucina-6/metabolismo , Leucocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Cannabinoide CB2/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
7.
Artículo en Inglés | MEDLINE | ID: mdl-28113722

RESUMEN

Ionotropic NMDA and AMPA glutamate receptors (iGluRs) play important roles in synaptic function under physiological and pathological conditions. iGluRs sub-synaptic localization and subunit composition are dynamically regulated by activity-dependent insertion and internalization. However, understanding the impact on synaptic transmission of changes in composition and localization of iGluRs is difficult to address experimentally. To address this question, we developed a detailed computational model of glutamatergic synapses, including spine and dendritic compartments, elementary models of subtypes of NMDA and AMPA receptors, glial glutamate transporters, intracellular calcium and a calcium-dependent signaling cascade underlying the development of long-term potentiation (LTP). These synapses were distributed on a neuron model and numerical simulations were performed to assess the impact of changes in composition and localization (synaptic vs extrasynaptic) of iGluRs on synaptic transmission and plasticity following various patterns of presynaptic stimulation. In addition, the effects of various pharmacological compounds targeting NMDARs or AMPARs were determined. Our results showed that changes in NMDAR localization have a greater impact on synaptic plasticity than changes in AMPARs. Moreover, the results suggest that modulators of AMPA and NMDA receptors have differential effects on restoring synaptic plasticity under different experimental situations mimicking various human diseases.

8.
Artículo en Inglés | MEDLINE | ID: mdl-27164603

RESUMEN

Ionotropic NMDA and AMPA glutamate receptors (iGluRs) play important roles in synaptic function under physiological and pathological conditions. iGluRs sub-synaptic localization and subunit composition are dynamically regulated by activity-dependent insertion and internalization. However, understanding the impact on synaptic transmission of changes in composition and localization of iGluRs is difficult to address experimentally. To address this question, we developed a detailed computational model of glutamatergic synapses, including spine and dendritic compartments, elementary models of subtypes of NMDA and AMPA receptors, glial glutamate transporters, intracellular calcium and a calcium-dependent signaling cascade underlying the development of long-term potentiation (LTP). These synapses were distributed on a neuron model and numerical simulations were performed to assess the impact of changes in composition and localization (synaptic vs extrasynaptic) of iGluRs on synaptic transmission and plasticity following various patterns of presynaptic stimulation. In addition, the effects of various pharmacological compounds targeting NMDARs or AMPARs were determined. Our results showed that changes in NMDAR localization have a greater impact on synaptic plasticity than changes in AMPARs. Moreover, the results suggest that modulators of AMPA and NMDA receptors have differential effects on restoring synaptic plasticity under different experimental situations mimicking various human diseases.

9.
J Neurosci Methods ; 257: 17-25, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26424508

RESUMEN

BACKGROUND: The resolution of a model describing the electrical activity of neural tissue and its propagation within this tissue is highly consuming in term of computing time and requires strong computing power to achieve good results. NEW METHOD: In this study, we present a method to solve a model describing the electrical propagation in neuronal tissue, using parareal algorithm, coupling with parallelization space using CUDA in graphical processing unit (GPU). RESULTS: We applied the method of resolution to different dimensions of the geometry of our model (1-D, 2-D and 3-D). The GPU results are compared with simulations from a multi-core processor cluster, using message-passing interface (MPI), where the spatial scale was parallelized in order to reach a comparable calculation time than that of the presented method using GPU. A gain of a factor 100 in term of computational time between sequential results and those obtained using the GPU has been obtained, in the case of 3-D geometry. Given the structure of the GPU, this factor increases according to the fineness of the geometry used in the computation. COMPARISON WITH EXISTING METHOD(S): To the best of our knowledge, it is the first time such a method is used, even in the case of neuroscience. CONCLUSION: Parallelization time coupled with GPU parallelization space allows for drastically reducing computational time with a fine resolution of the model describing the propagation of the electrical signal in a neuronal tissue.


Asunto(s)
Algoritmos , Simulación por Computador , Electricidad , Modelos Neurológicos , Neuronas/fisiología , Membrana Celular/fisiología , Gráficos por Computador , Espacio Extracelular/fisiología , Potenciales de la Membrana/fisiología , Tiempo
10.
Neurotoxicology ; 54: 140-152, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27108687

RESUMEN

Exposure to organophosphorus (OP) compounds, either pesticides or chemical warfare agents, represents a major health problem. As potent irreversible inhibitors of cholinesterase, OP may induce seizures, as in status epilepticus, and occasionally brain lesions. Although these compounds are extremely toxic agents, the search for novel antidotes remains extremely limited. In silico modeling constitutes a useful tool to identify pharmacological targets and to develop efficient therapeutic strategies. In the present work, we developed a new in silico simulator in order to predict the neurotoxicity of irreversible inhibitors of acetyl- and/or butyrylcholinesterase (ChE) as well as the potential neuroprotection provided by antagonists of cholinergic muscarinic and glutamate N-methyl-d-aspartate (NMDA) receptors. The simulator reproduced firing of CA1 hippocampal neurons triggered by exposure to paraoxon (POX), as found in patch-clamp recordings in in vitro mouse hippocampal slices. In the case of POX intoxication, it predicted a preventing action of the muscarinic receptor antagonist atropine sulfate, as well as a synergistic action with the non-competitive NMDA receptor antagonist memantine. These in silico predictions relative to beneficial effects of atropine sulfate combined with memantine were recapitulated experimentally in an in vivo model of POX in adult male Swiss mice using electroencephalic (EEG) recordings. Thus, our simulator is a new powerful tool to identify protective therapeutic strategies against OP central effects, by screening various combinations of muscarinic and NMDA receptor antagonists.


Asunto(s)
Simulación por Computador , Modelos Neurológicos , Síndromes de Neurotoxicidad/etiología , Organofosfatos/toxicidad , Paraoxon/toxicidad , Acetilcolinesterasa/metabolismo , Animales , Ondas Encefálicas/efectos de los fármacos , Reactivadores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Memantina/farmacología , Potenciales de la Membrana/efectos de los fármacos , Ratones , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , Oximas/farmacología , Compuestos de Piridinio/farmacología
11.
PLoS One ; 10(7): e0131985, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26134141

RESUMEN

The heat shock response (HSR) is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders.


Asunto(s)
Respuesta al Choque Térmico/fisiología , Enfermedades Neurodegenerativas/metabolismo , Neuronas/patología , Administración Oral , Animales , Astrocitos/citología , Encéfalo/metabolismo , Cromosomas Artificiales Bacterianos , Cuerpo Estriado/metabolismo , Femenino , Citometría de Flujo , Regulación de la Expresión Génica , Proteínas HSP90 de Choque Térmico/metabolismo , Hipocampo/patología , Masculino , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/patología , Neuronas/citología , Neuronas/metabolismo , Oligodendroglía/citología , Piridonas/química , Pirimidinas/química , ARN Mensajero/metabolismo
12.
Bull Cancer ; 90(8-9): 779-88, 2003.
Artículo en Francés | MEDLINE | ID: mdl-14609769

RESUMEN

Cell therapy can be defined as "the in vivo use of autologous, allogeneic or xenogeneic cells for the prevention, treatment or attenuation of disease". There have been major advances in this field in the last few years, leading to many clinical applications. Because of safety and ethical concerns, the therapeutic use of cells products justified to be regulated. In France, the law number 96-452 and the law number 98-535 defined a specific regulatory framework for these products: previous authorisation is required for the site of preparation of therapeutic cells product, for clinical trial relating to cell therapy products and for their therapeutic use. Some Cell therapy products could be considered as proprietary medicinal product. The authorisation for the site of preparation and for the clinical trial are granted by the French Health Products Agency ("Afssaps"). Depending on the status, the product could be authorised by Afssaps or by the European Agency for the Evaluation of Medicinal Products (EMEA). Whatever the status, the quality and security of these products should be controlled and the therapeutic use validated. In Europe, such products are currently regulated under the varying national laws of each member states. A European regulation must be defined for cell based products.


Asunto(s)
Trasplante de Células/legislación & jurisprudencia , Trasplante de Células/efectos adversos , Europa (Continente) , Francia , Seguridad
13.
Front Microbiol ; 4: 46, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23487495

RESUMEN

The antiviral activity of several cationic compounds - cetyltrimethylammonium bromide (CTAB), chitosan, nisin, and lysozyme - was investigated on the bacteriophage c2 (DNA head and non-contractile tail) infecting Lactococcus strains and the bacteriophage MS2 (F-specific RNA) infecting E. coli. Firstly, these activities were evaluated in a phosphate buffer pH 7 - 10 mM. The CTAB had a virucidal effect on the Lactococcus bacteriophages, but not on the MS2. After 1 min of contact with 0.125 mM CTAB, the c2 population was reduced from 6 to 1.5 log(pfu)/mL and completely deactivated at 1 mM. On the contrary, chitosan inhibited the MS2 more than it did the bacteriophages c2. No antiviral effect was observed for the nisin or the lysozyme on bacteriophages after 1 min of treatment. A 1 and 2.5 log reduction was respectively observed for nisin and lysozyme when the treatment time increased (5 or 10 min). These results showed that the antiviral effect depended both on the virus and structure of the antimicrobial compounds. The antiviral activity of these compounds was also evaluated in different physico-chemical conditions and in complex matrices. The antiviral activity of CTAB was impaired in acid pH and with an increase of the ionic strength. These results might be explained by the electrostatic interactions between cationic compounds and negatively charged particles such as bacteriophages or other compounds in a matrix. Milk proved to be protective suggesting the components of food could interfere with antimicrobial compounds.

14.
J Clin Invest ; 121(8): 3306-19, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21785217

RESUMEN

Huntington disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. Previous studies have proposed that activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1) may be of therapeutic benefit. However, the effect of disease progression on the HSR and the therapeutic potential of this pathway are currently unknown. Here, we used a brain-penetrating HSP90 inhibitor and physiological, molecular, and behavioral readouts to demonstrate that pharmacological activation of HSF1 improves huntingtin aggregate load, motor performance, and other HD-related phenotypes in the R6/2 mouse model of HD. However, the beneficial effects of this treatment were transient and diminished with disease progression. Molecular analyses to understand the transient nature of these effects revealed altered chromatin architecture, reduced HSF1 binding, and impaired HSR accompanied disease progression in both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. Taken together, our findings reveal that the HSR, a major inducible regulator of protein homeostasis and longevity, is disrupted in HD. Consequently, pharmacological induction of HSF1 as a therapeutic approach to HD is more complex than was previously anticipated.


Asunto(s)
Cromatina/química , Proteínas de Unión al ADN/fisiología , Respuesta al Choque Térmico/genética , Enfermedad de Huntington/metabolismo , Factores de Transcripción/fisiología , Animales , Núcleo Celular/metabolismo , Cromatina/metabolismo , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico , Enfermedad de Huntington/genética , Masculino , Ratones , Ratones Transgénicos , Fenotipo , Regulación hacia Arriba
15.
Behav Brain Res ; 225(1): 222-9, 2011 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-21820013

RESUMEN

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-ß peptide (Aß(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aß(1-40) or the control peptide Aß(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aß(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aß(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aß(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.


Asunto(s)
Péptidos beta-Amiloides/toxicidad , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/tratamiento farmacológico , Fragmentos de Péptidos/toxicidad , Fenilcarbamatos/uso terapéutico , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Donepezilo , Relación Dosis-Respuesta a Droga , Indanos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Piperidinas/uso terapéutico , Reconocimiento en Psicología/efectos de los fármacos , Rivastigmina
16.
Amyotroph Lateral Scler ; 8(4): 217-23, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17653919

RESUMEN

A transgenic animal model for anterior horn cell loss was established in 1994. This model is based on the insertion of a high copy number of disease-causing human Cu/Zn SOD mutations into the intact mouse genome. It serves to establish hypotheses for the pathogenesis of anterior horn cell death, but also to test potential pharmacological approaches to therapy in human ALS. Today, more than 100 -- published and unpublished -- compounds have been tested in this animal model, a large part of them being reported as successful. However, it proved to be difficult to translate these therapeutic successes in the animal model into human trials. Also, a number of disease-modifying strategies were difficult to reproduce, even by the same group. On the other hand, the step from mice to men means a huge investment for the sponsors of clinical trials and the scientific community. Therefore, establishment of standard methods for drug testing in ALS models is mandatory. In this workshop, clinical and preclinical researchers established in the field of ALS/MND met in Holland in March 2006 in order to establish guidelines for the community for drug testing in mouse models.


Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Animales , Humanos , Ratones , Ratones Transgénicos , Superóxido Dismutasa/genética
17.
Mov Disord ; 17(1): 13-9, 2002 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11835434

RESUMEN

Our study aimed to determine whether riluzole, which has shown efficacy as a disease-modifying agent in amyotrophic lateral sclerosis (ALS), is neuroprotective in a marmoset model of Parkinson's disease (PD). Reduction of energy demand by riluzole could be a rational neuroprotective strategy with good tolerability. The efficacy of riluzole was evaluated in marmosets by testing its ability to reduce MPTP-induced behavioral deficits and loss of dopaminergic nigral neurons. Marmosets were divided into two groups of four animals each: animals in Group 1 were injected twice with MPTP (2 mg/kg subcutaneous) and treated with riluzole (10 mg/kg per os b.i.d.), animals in Group 2 (controls) were injected with MPTP and with the vehicle of riluzole. A third group of marmosets which did not receive MPTP or riluzole drug was introduced for neurohistopathological studies (normal animals). Marmosets treated with riluzole preserved a better motor function and neurological performance through the 26 days of assessment when compared with the controls. Histologically, there was sparing of TH- and Nissl-stained nigral neurons and of TH-stained terminals in the striatum and the putamen in the group treated with riluzole compared to the controls. We conclude that riluzole protects dopaminergic neurons and reduces behavioral deficits in a marmoset model of PD.


Asunto(s)
Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Riluzol/uso terapéutico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Callithrix , Modelos Animales de Enfermedad , Dopamina/metabolismo , Dopaminérgicos/efectos adversos , Femenino , Inmunohistoquímica , Locomoción/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/farmacología , Cuerpos de Nissl/efectos de los fármacos , Cuerpos de Nissl/metabolismo , Cuerpos de Nissl/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Distribución Aleatoria , Riluzol/farmacología , Sustancia Negra/efectos de los fármacos
18.
Exp Neurol ; 176(1): 247-53, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12093102

RESUMEN

The effects of a chronic treatment with the anti-glutamate and sodium channel modulating neuroprotective agent riluzole on the degeneration of dopamine-containing neurons were studied in the brain of weaver mutant mice. In these animals, as in Parkinson's disease, dopaminergic neurons of the nigro-striatal pathway undergo spontaneous and progressive cell death. Homozygous weaver mice were orally treated twice a day with either 8 mg/kg riluzole or placebo for 2 months. Quantification of tyrosine-hydroxylase and dopamine-transporter axonal immunostaining in the striatum revealed that riluzole significantly increased the density of striatal dopaminergic nerve terminals. These results suggest that riluzole protects dopaminergic processes in the weaver mice and/or promotes their neuroplasticity.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Glicoproteínas de Membrana , Proteínas del Tejido Nervioso , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Canales de Potasio de Rectificación Interna , Riluzol/farmacología , Sustancia Negra/efectos de los fármacos , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Esquema de Medicación , Canales de Potasio Rectificados Internamente Asociados a la Proteína G , Homocigoto , Proteínas de Transporte de Membrana/biosíntesis , Ratones , Ratones Mutantes Neurológicos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Canales de Potasio/genética , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/patología , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tiempo , Tirosina 3-Monooxigenasa/biosíntesis
19.
Exp Neurol ; 184(1): 247-63, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14637096

RESUMEN

Several novel transgenic mouse models expressing different mutant APPs in combination with mutant PS1 have been developed. These models have been analyzed to investigate the formation and progressive alterations of dystrophic neurites (DNs) in relation to Abeta deposits. In the most aggressive model, Abeta deposits appear as early as 2.5 months of age. Maturation of DNs was qualitatively quite similar among models and in some respect reminiscent of human AD pathology. From the onset of deposition, most if not all Abeta deposits were decorated with a high number of APP-, ubiquitin-, and MnSOD-immunoreactive DNs. Phosphorylated Tau DNs, however, appeared at a much slower rate and were more restricted. Mitochondrial dysfunction markers were observed in DNs: the frequency and the density per deposit of DNs accumulating cytochrome c, cytochrome oxidase 1, and Bax progressively increased with age. Later, the burden of reactive DNs was reduced around large compact/mature deposits. In addition, the previously described phenomenon of early intraneuronal Abeta accumulation in our models was associated with altered expression of APP protein as well as oxidative and mitochondrial stress markers occasionally in individual neurons. The present study demonstrates that oxidative and mitochondrial stress factors are present at several phases of Abeta pathology progression, confirming the neuronal dysfunction in APP transgenic mice.


Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Proteínas de la Membrana/genética , Neuritas/patología , Placa Amiloide/patología , Animales , Humanos , Inmunoensayo , Inmunohistoquímica , Mediciones Luminiscentes , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Mutación/genética , Placa Amiloide/genética , Plásmidos/genética , Presenilina-1 , Estrés Fisiológico/patología , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Proteínas tau/metabolismo
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