GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR BUT NOT TRANSFORMING GROWTH-FACTOR BETA-3 PREVENTS DELAYED DEGENERATION OF NIGRAL DOPAMINERGIC-NEURONS FOLLOWING STRIATAL 6-HYDROXYDOPAMINE LESION

Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor beta 3 (TGF-beta 3) are members of the TGF-beta superfamily with high neurotrophic activity on cultured nigral dopamine neurons. We investigated the effects of intracerebral administration of GDNF and TGF-beta 3 on the delayed cell death of the dopamine neurons in the rat substantia nigra following 6-hydroxydopamine lesions of dopaminergic terminals in the striatum. Fluorescent retrograde tracer injections and tyrosine hydroxylase immunocytochemistry demonstrated nigral degeneration with an onset 1 week after lesion, leading to extensive death of nigral neurons 4 weeks postlesion. Administration of recombinant human GDNF for 4 weeks over the substantia nigra at a cumulative dose of 140 mu g, starting on the day of lesion, completely prevented nigral cell death and atrophy, while a single injection of 10 mu g 1 week postlesion had a partially protective effect, Continuous administration of TGF-beta 3, starting on the day of lesion surgery, did not affect nigral cell death or atrophy, These findings support the notion that GDNF, but not TGF-beta 3, is a potent neurotrophic factor for nigral dopamine neurons in vivo.