Diminished glutathione levels cause spontaneous and mitochondria-mediated cell death in neurons from trisomy 16 mice: A model of Down's syndrome

It has been suggested that the increased neuronal death in cultures from tr isomy 16 (Ts16) mice, a model of Down's syndrome, might result from a dimin ished concentration of reduced glutathione (GSH). In this study we used mic rofluorometric techniques to investigate the effect of GSH levels on neuron al survival in diploid and Ts16 cultures. Addition of the GSH precursors cy steine and cystine and the antioxidant tocopherol to the culture medium inc reased the GSH concentration up to 126.0% in diploid and up to 111.9% in Ts 16 neurons. Moreover, we observed a reduced spontaneous neuronal death rate in diploid and Ts16 cultures, Following the application of 50-100 mu M glu tamate to culture medium, we found a GSH increase in the presence of cystei ne, cystine, tocopherol, and cyclosporin A, an inhibitor of mitochondrial p ermeability transition (diploid, 105.8-110.8%; Ts16, 83.1-96.3%). However, only tocopherol and cyclosporin A had a protective effect on glutamate-indu ced neuronal death, The results suggest that reduced GSH levels affect the increase of a spontaneous and a mitochondria-mediated, cyclosporin A-sensit ive type of neuronal cell death, Therefore, elevating intracellular GSH con centration may have neuroprotective effects in Down's syndrome and Alzheime r's disease.