GLIA PROTECT FETAL MIDBRAIN DOPAMINE NEURONS IN CULTURE FROM L-DOPA TOXICITY THROUGH MULTIPLE MECHANISMS

Mesencephalic glia produce soluble factors that protect dopamine neuro ns from L-DOPA toxicity. The chemical composition of these soluble fac tors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different m olecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidan ts. Protective effects were evaluated according to the number of tyros ine hydroxylase immunoreactive cells, high affinity dopamine uptake an d levels of quinones. Both fractions of glia conditioned medium, small er and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger m olecules, was more effective than the fraction of larger molecular siz e, that contains large neurotrophic peptides. Among the neurotrophic f actors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the co ncentration found in glia conditioned medium, provided partial protect ive effect against L-DOPA toxicity. Glutathione, had neurotrophic effe cts on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxi city by glia conditioned medium is mediated by several compounds inclu ding neurotrophic factors and small antioxidants.