Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Abstract: l ‐DOPA is toxic to catecholamine neurons in culture, but the toxicity is reduced by exposure to astrocytes. We tested the effect of l ‐DOPA on dopamine neurons using postnatal ventral midbrain neuron/cortical astrocyte cocultures in serum‐free, glia‐conditioned medium. l ‐DOPA (50 µ M ) protected against dopamine neuronal cell death and increased the number and branching of dopamine processes. In contrast to embryonically derived glia‐free cultures, where l ‐DOPA is toxic, postnatal midbrain cultures did not show toxicity at 200 µ M l ‐DOPA. The stereoisomer d ‐DOPA (50–400 µ M ) was not neurotrophic. The aromatic amino acid decarboxylase inhibitor carbidopa (25 µ M ) did not block the neurotrophic effect. These data suggest that the neurotrophic effect of l ‐DOPA is stereospecific but independent of the production of dopamine. However, l ‐DOPA increased the level of glutathione. Inhibition of glutathione peroxidase by l ‐buthionine sulfoximine (3 µ M for 24 h) blocked the neurotrophic action of L‐DOPA. N ‐Acetyl‐ l ‐cysteine (250 µ M for 48 h), which promotes glutathione synthesis, had a neurotrophic effect similar to that of l ‐DOPA. These data suggest that the neurotrophic effect of l ‐DOPA may be mediated, at least in part, by elevation of glutathione content.