RESUMEN
Because NMDA complex and mitochondrial function are related, we hypothesized memantine would influence mitochondrial function. We addressed this in vitro by studying the effects of chronic and acute memantine exposures on mitochondrial function. For acute exposure experiments, mitochondria were isolated from NT2 cells and assayed for electron transport chain (ETC) enzyme function and peroxide production in buffers containing up to 60uM memantine. For chronic exposure experiments, NT2 cells were maintained for at least two weeks in medium containing up to 60uM memantine, following which we assayed cells or their mitochondria for ETC enzyme activities, cytochrome oxidase protein levels, oxidative stress, calcium levels, and mitochondrial DNA levels. The ability of the NMDA receptor antagonist aminophosphonovaleric acid (APV) to modify memantine's mitochondrial effects was evaluated. Acute and chronic memantine similarly affected complex I (increased at high concentrations) and IV (decreased at high concentrations) V(max) activities. APV did not alter the effects of chronic memantine exposure on citrate synthase and complex IV. We detected a lower mitochondrial peroxide production rate with acute exposure, and an increased mitochondrial peroxide production rate with chronic exposure. Micromolar memantine concentrations affect mitochondria, some of these effects are directly mediated, and acute and chronic effects may differ.
Asunto(s)
Memantina/farmacología , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Calcio/metabolismo , Línea Celular Tumoral , Citrato (si)-Sintasa/metabolismo , Relación Dosis-Respuesta a Droga , Transporte de Electrón , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Mitocondrias/enzimología , Mitocondrias/metabolismo , Consumo de Oxígeno/efectos de los fármacosRESUMEN
Thiazolidinediones alter cell energy metabolism. They are used to treat or are being considered for the treatment of disorders that feature mitochondrial impairment. Their mitochondrial effects, however, have not been comprehensively studied under long-term exposure conditions. We used the human neuron-like NT2 cell line to directly assess the long-term effects of a thiazolidinedione drug, pioglitazone, on mitochondria. At micromolar concentrations, pioglitazone increased mitochondrial DNA (mtDNA) content, levels of mtDNA and nuclear-encoded electron transport chain subunit proteins, increased oxygen consumption, and elevated complex I and complex IV V(max) activities. Pioglitazone treatment was also associated with increased cytoplasmic but reduced mitochondrial peroxide levels. Our data suggest that pioglitazone induces mitochondrial biogenesis and show that pioglitazone reduces mitochondrial oxidative stress in a neuron-like cell line. For these reasons pioglitazone may prove useful in the treatment of mitochondriopathies.
Asunto(s)
Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Tiazolidinedionas/farmacología , Línea Celular , Respiración de la Célula/efectos de los fármacos , ADN Mitocondrial , Transporte de Electrón/efectos de los fármacos , Humanos , Mitocondrias/fisiología , Neuronas/citología , Neuronas/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Pioglitazona , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Assisting current smokers to progress towards stopping smoking entails identifying their readiness to stop and understanding the factors that may influence their readiness. Relations were established between certain predictor variables (intensity of smoking, age at initiation, duration of smoking, and gender) and stages of readiness to change smoking behaviour in Kiev, Ukraine. METHODS: Analysis was based on a convenient sample of 536 current smokers who completed a stages-of-change questionnaire in a public square in the centre of Kiev's business district, between 22 and 25 July 2000. Frequency distributions, odds ratios, the Kolmogorov-Smirnov test and the Wilcoxon rank-sum test were used to summarize and describe the data. Tests of significance were based on the 0.05 level. RESULTS: The majority of participants (56.1%) were categorized as precontemplative. Less than 20% of the subjects were prepared for action to change smoking behaviour. Later age at smoking initiation was associated with fewer cigarettes smoked per day. Females were more likely then males to seriously consider cutting down the number of cigarettes they smoked. However, males were more likely to have intentionally quit smoking for at least one day within the past year. CONCLUSION: Information on stages of readiness to stop smoking provided by this study may be useful for improving the effectiveness of smoking cessation programmes in Kiev.