GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo

Glial cell line-derived neurotrophic factor (GDNF), a novel member of the TGF-beta superfamily, has been shown to promote the survival and morphological differentiation of fetal dopamine neurons in culture and increase dopamine levels and metabolism in adult rats. Since several other trophic factors are able to rescue specific populations of mature CNS neurons following injury, the present study was designed to investigate a possible neuroprotective role by GDNF for midbrain dopamine neurons in rats exposed to the neurotoxin 6-hydroxydopamine (6-OHDA). Prior to surgery, young adult male Fisher 344 rats were divided into the following groups (n = 7-8/group): (1) intranigral saline + intranigral 6-OHDA; (2) intranigral GDNF + intranigral 6-OHDA; (3) intranigral saline + intrastriatal 6-OHDA; and (4) intranigral GDNF + intrastriatal 6-OHDA. The saline treated groups received a single 2 microliters intranigral injection of phosphate buffered saline (PBS) while the GDNF treated rats received 10 micrograms/2 microliters GDNF in PBS. Twenty-four hours later, the animals received a unilateral 4 micrograms/microliters 6-OHDA infusion either into the substantia nigra or striatum. The rats were sacrificed two weeks postsurgery and the brains processed for tyrosine hydroxylase (TH) immunocytochemistry. Representative TH immunoreactive (TH-IR) sections were also counterstained with hematoxylin and eosin to determine the total number of neurons remaining in the substantia nigra pars compacta and ventral tegmental area. In the nigral lesion groups, there was significantly less loss of TH-IR neurons in the substantia nigra pars compacta of GDNF (47% survival) vs. PBS (9% survival) treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)