RESUMEN
Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.
Asunto(s)
Acetilcisteína/farmacología , Conducta Animal/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Enfermedad de Huntington/metabolismo , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Transportador 2 de Aminoácidos Excitadores/efectos de los fármacos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Marcha/efectos de los fármacos , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Actividad Motora/efectos de los fármacos , Tamaño de los ÓrganosRESUMEN
Impaired cognitive function is part of an array of neurologic manifestations seen in patients with end stage renal disease. We investigated whether a difference exists in mental performance between patients on hemodialysis and on CAPD. The trial test A was administered in standardized fashion, and the time required to complete the test was used as a function of mental performance. A group of age and sex matched healthy controls was included for comparison. The results indicate that performance in the trail test A was markedly different among the three groups; controls did the test in 30.7 +/- 2.4 sec (n = 17), CAPD in 47.2 +/- 6.4 (p less than 0.05) and hemodialysis patients in 82.6 +/- 11 (p less than 0.005). Patients on CAPD completed the test significantly faster than those on hemodialysis (p less than 0.05). This observation of a significantly better mental performance by patients in CAPD than in patients in hemodialysis is likely to be multifactorial, and its significance is unclear, but this may be of interest to the clinician and patients contemplating different dialysis modalities.
Asunto(s)
Procesos Mentales , Diálisis Peritoneal Ambulatoria Continua , Humanos , Masculino , Persona de Mediana Edad , Pruebas Psicológicas , Diálisis RenalRESUMEN
Nervous system dysfunction remains a major cause of disability in patients with end stage renal disease. The mechanisms remain unclear, but elevated levels of parathyroid hormone (PTH) have been proposed to act as a neurotoxin in uremia. Previous studies have mainly used electroencephalographic techniques to assess mental performance in patients in dialysis. This study utilized the trail test A and the Pennsylvania bimanual dexterity work sample to evaluate mental performance of patients in CAPD and to correlate their performance with parathyroid hormone levels. Ten male patients from the same CAPD unit, with comparable dialysis dose, underwent standardized testing. Subjects had a mean +/- SE age of 50.8 +/- 3.66 years and had been on CAPD for a mean of 42.4 +/- 12.2 months. Each used 10-12 liters of dialysis per day, with a mean peritoneal dialysis index of 1.04 +/- 0.05 and Kt/V (UN/wk) of 2.35 +/- 0.39. Mental performance of patients with lower intact PTH levels 151.7 +/- 20.8 ng/ml (Group 1) was 34.4 +/- 2.8 min in the trail test A and patients with the higher PTH-mm level (414.0 +/- 21.4 ng/ml) was 58.2 +/- 10.8 min (p = 0.06). Whereas the bi-manual dexterity test was completed in 7.27 +/- 0.5 min by Group 1 and in 11.1 +/- 0.2 by Group 2 (p = 0.003). This study favors the hypothesis that PTH levels may be associated with the impaired mental performance observed in patients with end stage renal disease.