ASTROCYTE-MEDIATED ENHANCEMENT OF NEURONAL SURVIVAL IS ABOLISHED BY GLUTATHIONE DEFICIENCY

Astrocytes promote the survival of neurons. Conditions characterized b y loss of neurons, such as aging and aging-related neurodegenerative d isorders, are accompanied by both disturbances in astrocyte-neuron int eractions and signs of oxidative damage. Neuronal glutathione, a major antioxidant in the brain, is maintained by astrocytes and brain level s of glutathione are reduced in named conditions. Therefore, we focuse d on a possible link between glutathione deficiency and loss of astroc yte-derived neuronal support. For this purpose, we used a coculture sy stem consisting of rat striatal astrocytes and mesencephalic, dopamine rgic (DAergic) neurons. Using tyrosine hydroxylase immunocytochemistry and radiolabeled dopamine uptake as parameters, an increase in the nu mber and outgrowth of DAergic neurons was noted in cocultures as compa red to cultures of mesencephalic neurons alone. This enhanced survival of DAergic neurons in cocultures was abolished following depletion of glutathione with buthionine sulfoximine. As demonstrated by glial fib rillary acidic protein immunocytochemistry and a microtiter tetrazoliu m assay, under these conditions no change in astrocyte survival occurr ed. However, glutathione depletion in cocultures was accompanied by lo ss of astrocyte-mediated neuroprotection against hydrogen peroxide tox icity. Thus, our results indicate that glutathione is important for th e maintenance of the neuronal support function of astrocytes and that glutathione deficiency in the brain may lead to enhanced vulnerability of neurons to (oxidative) damage. (C) 1997 Elsevier Science B.V.