GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR SUPPORTS SURVIVAL OF INJURED MIDBRAIN DOPAMINERGIC-NEURONS

Glial cell-lined derived neurotrophic factor (GDNF) has been shown to promote survival of developing mesencephalic dopaminergic neurons in v itro. In order to determine if there is a positive effect of GDNF on i njured adult midbrain dopaminergic neurons in situ, we have carried ou t experiments in which a single dose of GDNF was injected into the sub stantia nigra following a unilateral lesion of the nigrostriatal syste m. Rats were unilaterally lesioned by a single stereotaxic injection o f 6-hydroxydopamine (6-OHDA; 9 mu g/4 mu l normal saline with 0.02% as corbate) into the medial forebrain bundle and tested weekly for apomor phine-induced (0.05 mg/kg s.c.) contralateral rotation behavior. Rats that manifested >300 turns/hour received a nigral injection of 100 mu g GDNF, or cytochrome C as a control, 4 weeks following the 6-OHDA les ion. Rotation behavior was quantified weekly for 5 weeks after GDNF. R ats were subsequently anesthetized, transcardially perfused, and proce ssed for tyrosine hydroxylase immunohistochemistry. It was found that 100 mu g GDNF decreased apomorphine-induced rotational behavior by mor e than 85%. Immunohistochemical studies revealed that tyrosine hydroxy lase immunoreactivity was equally reduced in the striatum ipsilateral to the lesion in both cytochrome C and GDNF-injected animals. In contr ast, large increments in tyrosine hydroxylase immunoreactivity were ob served in the substantia nigra of animals treated with 100 mu g of GDN F, with a significant increase in numbers of tyrosine hydroxylase-immu noreactive cell bodies and neurites as well as a small increase in the cell body area of these neurons. The results suggest that GDNF can ma intain the dopaminergic neuronal phenotype in a number of nigral neuro ns following a unilateral nigrostriatal lesion in the rat. (C) 1995 Wi ley-Liss, Inc.