Neurodegeneration or neuroprotection: the pivotal role of astrocytes.

Formation of nitric oxide (NO), by astrocytes, has been suggested to contribute, via impairment of mitochondrial function, to the neurodegnerative process. Thus co-culture of neuronal cells with NO-generating astrocytes leads to a loss of mitochondrial function, as reflected by diminished activities of complexes IV and II+III. However, such damage may in the first instance be limited due to upregulation of neuronal glutathione metabolism as a result of metabolic trafficking of glutathione from the astrocyte to neurone. Furthermore, exposure of astrocytes to NO leads to increased glutathione metabolism resulting in the preservation of glutathione precursors for neuronal utilization. Failure of glutathione trafficking could render neuronal cells particularly susceptible to NO, leading to cell death. In addition, depletion with time of the nitric oxide synthase cofactor, tetrahydrobiopterin, may result in the astrocytic generation of more potent oxidizing species, which could contribute to the neurodegenerative process.