Abstract
We have recently shown that the hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) is neuroprotective in rodent stroke models, and that this action appears to be mediated via a neuronal G-CSF receptor. Here, we report that the G-CSF receptor is expressed in rodent dopaminergic substantia nigra neurons, suggesting that G-CSF might be neuroprotective for dopaminergic neurons and a candidate molecule for the treatment of Parkinson's disease. Thus, we investigated protective effects of G-CSF in 1-methyl-4-phenylpyridinium (MPP+)-challenged PC12 cells and primary neuronal midbrain cultures, as well as in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Substantial protection was found against MPP+-induced dopaminergic cell death in vitro. Moreover, subcutaneous application of G-CSF at a dose of 40 microg/Kg body weight daily over 13 days rescued dopaminergic substantia nigra neurons from MPTP-induced death in aged mice, as shown by quantification of tyrosine hydroxylase-positive substantia nigra cells. Using HPLC, a corresponding reduction in striatal dopamine depletion after MPTP application was observed in G-CSF-treated mice. Thus our data suggest that G-CSF is a novel therapeutic opportunity for the treatment of Parkinson's disease, because it is well-tolerated and already approved for the treatment of neutropenic conditions in humans.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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3,4-Dihydroxyphenylacetic Acid / metabolism
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Animals
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Blotting, Northern / methods
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Brain / cytology
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Brain / drug effects
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Brain / metabolism
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Cell Count / methods
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Cells, Cultured
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Chromatography, High Pressure Liquid / methods
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Disease Models, Animal
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Dopamine / metabolism
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Embryo, Mammalian
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Gene Expression / drug effects
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Gene Expression / physiology
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Granulocyte Colony-Stimulating Factor / therapeutic use*
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Green Fluorescent Proteins
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Homovanillic Acid / metabolism
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Immunohistochemistry / methods
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / therapeutic use*
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / prevention & control*
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Receptors, Granulocyte Colony-Stimulating Factor / genetics
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Receptors, Granulocyte Colony-Stimulating Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Transfection / methods
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Neuroprotective Agents
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RNA, Messenger
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Receptors, Granulocyte Colony-Stimulating Factor
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3,4-Dihydroxyphenylacetic Acid
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Granulocyte Colony-Stimulating Factor
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Green Fluorescent Proteins
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Tyrosine 3-Monooxygenase
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Dopamine
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Homovanillic Acid