Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration
The primate striatum contains tyrosine hydroxylase (TH)-immunoreactive (ir) neurons, the numbers of which are augmented after dopamine depletion. Glial cell line-derived neurotrophic factor (GDNF) strongly modulates the viability and phenotypic expression of dopamine ventral mesencephalic neurons. The effect of GDNF on TH-ir neurons intrinsic to the striatum has yet to be investigated. In the present study, stereological counts of TH-ir striatal neurons in aged and parkinsonian nonhuman primates revealed that GDNF delivered via a lentiviral vector (lenti-) further increased the number of these cells. Aged monkeys treated with lenti-GDNF displayed an eightfold increase in TH-ir neurons relative to lenti-beta-galactosidase-treated monkeys. Unilateral 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine treatment alone in young monkeys resulted in a bilateral eightfold increase in TH-ir striatal cells. This effect was further magnified sevenfold on the side of lenti-GDNF treatment. These cells colocalized with the neuronal marker neuronal-specific nuclear protein. Some of these cells colocalized with GDNF-ir, indicating that an alteration in phenotype may occur by the direct actions of this trophic factor. Thus, GDNF may mediate plasticity in the dopamine-depleted primate brain, which may serve to compensate for cell loss by converting striatal neurons to a dopaminergic phenotype.
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Keywords: 1-Methyl-4-phenyl-1 ; 2 ; 3 ; 6-tetrahydropyridine/pharmacology ; Aging ; Animals ; Antiparkinson Agents/*metabolism ; Cell Count ; Corpus Striatum/*cytology/drug effects/enzymology ; Dopamine/*metabolism ; Dopamine Agents/pharmacology ; Fluorescent Antibody Technique ; Gene Therapy ; Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor ; Haplorhini ; Lentivirus/genetics ; Microscopy ; Fluorescence ; *Nerve Growth Factors ; Nerve Tissue Proteins/*genetics ; Neurons/cytology/drug effects/enzymology ; Parkinson Disease/enzymology/*pathology/therapy ; Substantia Nigra/*cytology/drug effects/enzymology ; Tyrosine 3-Monooxygenase/analysis/immunology ; 3
Department of Neurological Sciences, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Record created on 2008-08-27, modified on 2016-08-08