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 vitro. In order to determine if there is a positive effect of GDNF on injured adult midbrain dopaminergic neurons in situ, we have carried out experiments in which a single dose of GDNF was injected into the substantia nigra following a unilateral lesion of the nigrostriatal system. Rats were unilaterally lesioned by a single stereotaxic injection of 6-hydroxydopamine (6-OHDA; 9 micrograms/4 microliters normal saline with 0.02% ascorbate) into the medial forebrain bundle and tested weekly for apomorphine-induced (0.05 mg/kg s.c.) contralateral rotation behavior. Rats that manifested > 300 turns/hour received a nigral injection of 100 micrograms GDNF, or cytochrome C as a control, 4 weeks following the 6-OHDA lesion. Rotation behavior was quantified weekly for 5 weeks after GDNF. Rats were subsequently anesthetized, transcardially perfused, and processed for tyrosine hydroxylase immunohistochemistry. It was found that 100 micrograms GDNF decreased apomorphine-induced rotational behavior by more than 85%. Immunohistochemical studies revealed that tyrosine hydroxylase immunoreactivity was equally reduced in the striatum ipsilateral to the lesion in both cytochrome C and GDNF-injected animals. In contrast, large increments in tyrosine hydroxylase immunoreactivity were observed in the substantia nigra of animals treated with 100 micrograms of GDNF, with a significant increase in numbers of tyrosine hydroxylase-immunoreactive cell bodies and neurites as well as a small increase in the cell body area of these neurons. The results suggest that GDNF can maintain the dopaminergic neuronal phenotype in a number of nigral neurons following a unilateral nigrostriatal lesion in the rat.
Bowenkamp
K E
KE
Department of Pharmacology, School of Dentistry, University of Colorado Health Sciences Center, Denver 80262, USA.
Hoffman
A F
AF
Gerhardt
G A
GA
Henry
M A
MA
Biddle
P T
PT
Hoffer
B J
BJ
Granholm
A C
AC
D000818:Animals; D001058:Apomorphine; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000033:anatomy & histology / Q000166:cytology* / Q000187:drug effects; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine; D051381:Rats; D011916:Rats, Inbred F344; D013239:Stereotyped Behavior / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine