Glial Cell Line-Derived Neurotrophic Factor but not Transforming Growth Factor β3 Prevents Delayed Degeneration of Nigral Dopaminergic Neurons Following Striatal 6-Hydroxydopamine Lesion

Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor β3 (TGF-β3) are members of the TGF-β superfamily with high neurotrophic activity on cultured nigral dopamine neurons. We investigated the effects of intracerebral administration of GDNF and TGF-β3 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 on-set 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 μg, starting on the day of lesion, completely prevented nigral cell death and atrophy, while a single injection of 10 μg 1 week postlesion had a partially protective effect. Continuous administration of TGF-β3, 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-β3, is a potent neurotrophic factor for nigral dopamine neurons in vivo.