Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Bone Marrow Transplant ; 47(7): 946-51, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22056644

RESUMO

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Terapia de Imunossupressão/métodos , Esclerose Múltipla/terapia , Adulto , Soro Antilinfocitário/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Esclerose Múltipla/cirurgia , Transplante Autólogo , Resultado do Tratamento , Irradiação Corporal Total
2.
J Pharmacol Exp Ther ; 293(2): 480-6, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10773018

RESUMO

In central neurons, glutamate receptor activation causes massive calcium influx and induces a mitochondrial depolarization, which is partially blocked by cyclosporin A, suggesting a possible activation of the mitochondrial permeability transition pore (PTP) as a mechanism. It has been recently reported that tamoxifen (an antiestrogen chemotherapeutic agent) blocks the PTP in isolated liver mitochondria, similar to cyclosporin A. In this study, we tested whether tamoxifen inhibits the mitochondrial depolarization induced by glutamate receptor activation in intact cultured neurons loaded with the fluorescent dye 5,5',6,6'-tetrachloro-1,1',3, 3'-tetraethylbenzimidazolylcarbocyanine iodide. This dye reports disruptions in mitochondrial membrane potential, which can be caused by PTP activation. We found that glutamate (100 microM for 10 min) causes a robust mitochondrial depolarization that is partially inhibited by tamoxifen. The maximum inhibitory concentration of tamoxifen was 0.3 microM, with concentrations higher and lower than 0.3 microM being less effective. However, although tamoxifen (0.3 microM) blocked glutamate-induced mitochondrial depolarization, it did not inhibit glutamate-induced neuronal death, in contrast to the PTP inhibitor cyclosporin A. A relatively high concentration of tamoxifen (100 microM) caused mitochondrial depolarization itself and was neurotoxic. These data suggest that tamoxifen may be an inhibitor of the PTP in intact neurons. However, the lack of specificity of most PTP inhibitors, and the difficulty in measuring PTP in intact cells, preclude definite conclusions about the role of PTP in excitotoxic injury.


Assuntos
Antineoplásicos Hormonais/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/farmacologia , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/toxicidade , Benzimidazóis , Carbocianinas , Morte Celular/efeitos dos fármacos , Células Cultivadas , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Antagonistas de Aminoácidos Excitatórios/toxicidade , Corantes Fluorescentes , Histocitoquímica , Masculino , Malonatos/toxicidade , Potenciais da Membrana/efeitos dos fármacos , Membranas/efeitos dos fármacos , Neostriado/citologia , Neostriado/efeitos dos fármacos , Neurônios/ultraestrutura , Permeabilidade/efeitos dos fármacos , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tamoxifeno/toxicidade
3.
Neuroscience ; 86(1): 279-90, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9692761

RESUMO

Several inhibitors of mitochondrial complex II cause neuronal death in vivo and in vitro. The goal of the present work was to characterize in vitro the effects of malonate (a competitive blocker of the complex) which induces neuronal death in a pattern similar to that seen in striatum in Huntington's disease. Exposure of striatal and cortical cultures from embryonic rat brain for 24 h to methylmalonate, a compound which produces malonate intracellularly, led to a dose-dependent cell death. Methylmalonate (10 mM) caused >90% mortality of neurons although cortical cells were unexpectedly more vulnerable. Cell death was attenuated in a medium containing antioxidants. Further characterization revealed that DNA laddering could be detected after 3 h of treatment. Morphological observations (videomicroscopy and Hoechst staining) showed that both necrotic and apoptotic cell death occurred in parallel; apoptosis was more prevalent. A decrease in the ATP/ADP ratio was observed after 3 h of treatment with 10 mM methylmalonate. In striatal cultures it occurred concomitantly with a decline in GABA and a rise in aspartate content and the aspartate/glutamate ratio. Changes in ion concentrations were measured in similar cortical cultures from mouse brain. Neuronal [Na+]i increased while [K+]i and membrane potential decreased after 20 min of continuous incubation in 10 mM methylmalonate. These changes progressed with time, and a rise in [Ca2+]i was also observed after 1 h. The results demonstrate that malonate collapses cellular ion gradients, restoration of which imposes an additional load on the already compromised ATP-generation machinery. An early elevation in [Ca2+]i may trigger an increase in activity of proteases, lipases and endonucleases and production of free radicals and DNA damage which, ultimately, leads to cells death. The data also suggest that maturational and/or extrinsic factors are likely to be critical for the increased vulnerability of striatal neurons to mitochondrial inhibition in vivo.


Assuntos
Apoptose , Encéfalo/citologia , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Ácido Metilmalônico/toxicidade , Neurônios/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ácido Aspártico/metabolismo , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Complexo II de Transporte de Elétrons , Feto , Ácido Glutâmico/metabolismo , Cinética , Camundongos , Microscopia de Vídeo , Complexos Multienzimáticos/antagonistas & inibidores , Neurônios/metabolismo , Neurônios/patologia , Oxirredutases/antagonistas & inibidores , Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Sódio/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismo
4.
J Neurochem ; 70(6): 2406-15, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9603205

RESUMO

Intrastriatal injections of the mitochondrial toxins malonate and 3-nitropropionic acid produce selective cell death similar to that seen in transient ischemia and Huntington's disease. The extent of cell death can be attenuated by pharmacological or surgical blockade of cortical glutamatergic input. It is not known, however, if dopamine contributes to toxicity caused by inhibition of mitochondrial function. Exposure of primary striatal cultures to dopamine resulted in dose-dependent death of neurons. Addition of medium supplement containing free radical scavengers and antioxidants decreased neuronal loss. At high concentrations of the amine, cell death was predominantly apoptotic. Methyl malonate was used to inhibit activity of the mitochondrial respiratory chain. Neither methyl malonate (50 microM) nor dopamine (2.5 microM) caused significant toxicity when added individually to cultures, whereas simultaneous addition of both compounds killed 60% of neurons. Addition of antioxidants and free radical scavengers to the incubation medium prevented this cell death. Dopamine (up to 250 microM) did not alter the ATP/ADP ratio after a 6-h incubation. Methyl malonate, at 500 microM, reduced the ATP/ADP ratio by approximately 30% after 6 h; this decrease was not augmented by coincubation with 25 microM dopamine. Our results suggest that dopamine causes primarily apoptotic death of striatal neurons in culture without damaging cells by an early adverse action on oxidative phosphorylation. However, when combined with minimal inhibition of mitochondrial function, dopamine neurotoxicity is markedly enhanced.


Assuntos
Corpo Estriado/efeitos dos fármacos , Dopamina/toxicidade , Malonatos/toxicidade , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Trifosfato de Adenosina/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Benzazepinas/farmacologia , Células Cultivadas , Corpo Estriado/metabolismo , Corpo Estriado/ultraestrutura , DNA/análise , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Sinergismo Farmacológico , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Sequestradores de Radicais Livres/farmacologia , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/ultraestrutura , Nomifensina/farmacologia , Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Fatores de Tempo , Gravação em Vídeo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA