Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons

Authors

  • Kathryn E. Bowenkamp,

    1. Department of Pharmacology, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
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  • Alexander F. Hoffman,

    1. Department of Pharmacology, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
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  • Greg A. Gerhardt,

    1. Department of Pharmacology, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    2. Department of Psychiatry, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    3. Neuroscience Training Program, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
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  • Michael A. Henry,

    1. School of Medicine, and Department of Basic Science, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
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  • Paul T. Biddle,

    1. School of Medicine, and Department of Basic Science, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
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  • Barry J. Hoffer,

    1. Department of Pharmacology, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    2. Department of Psychiatry, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    3. Neuroscience Training Program, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
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  • Ann-Charlotte E. Granholm

    Corresponding author
    1. Department of Pharmacology, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    2. Neuroscience Training Program, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    3. School of Medicine, and Department of Basic Science, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262
    • Department of Basic Science, Campus box C286, University of Colorado HSC, Denver CO 80262
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Abstract

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 μg/4 μl 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 μg 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 μg 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 μg 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.

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