Macrophage-mediated GDNF Delivery Protects Against Dopaminergic Neurodegeneration: A Therapeutic Strategy for Parkinson's Disease
Male
Dopamine
Neurotoxins
Enzyme-Linked Immunosorbent Assay
Eating
Mice
03 medical and health sciences
Drug Discovery
Genetics
Animals
Glial Cell Line-Derived Neurotrophic Factor
Molecular Biology
Cells, Cultured
Chromatography, High Pressure Liquid
Pharmacology
0303 health sciences
Macrophages
Body Weight
Parkinson Disease
Flow Cytometry
3. Good health
Mice, Inbred C57BL
Substantia Nigra
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Nerve Degeneration
Molecular Medicine
DOI:
10.1038/mt.2010.107
Publication Date:
2010-06-08T14:47:24Z
AUTHORS (8)
ABSTRACT
Glial cell line-derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson's disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood-brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell-derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH(+) terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.
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