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Continuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft's ability to improve spontaneous motor behavior in parkinsonian rats.
- Source :
-
Neuroscience [Neuroscience] 2006 Aug 11; Vol. 141 (1), pp. 521-31. Date of Electronic Publication: 2006 May 11. - Publication Year :
- 2006
-
Abstract
- Functional recovery following intrastriatal transplantation of fetal dopaminergic neurons in animal models of Parkinson's disease is, at least in part, dependent on the number of surviving dopaminergic neurons and the degree of graft-derived dopaminergic reinnervation of the host striatum. In the present study, we analyzed whether continuous exposure of glial cell line-derived neurotrophic factor (GDNF) to mature dopaminergic grafts could further boost the functional outcome of widespread intrastriatal dopaminergic grafts. Rats with dopamine-denervating lesions received multiple intrastriatal transplants of fetal dopaminergic cells and graft-induced behavioral effects were analyzed in drug-induced and spontaneous motor behaviors. At three months after grafting, animals received intrastriatal injections of recombinant lentiviral vectors encoding for either human GDNF or the green fluorescent protein. Continuous exposure of GDNF to the grafts did not boost the functional recovery beyond what was observed in the control animals. Rather, in some of the spontaneous motor behaviors, animals in the GDNF-group showed deterioration as compared with control animals, and this negative effect of GDNF was associated with a down-regulation of the tyrosine hydroxylase enzyme. Based on these and our earlier results, we propose that intrastriatal administration of GDNF at the time of or shortly after grafting is highly effective in initially promoting the cell survival and fiber outgrowth from the grafts. However, once the grafts are mature, GDNF's ability to boost dopaminergic neurotransmission follows the same dynamics as for the native nigral dopaminergic neurons, which appears to be dependent on the concentration of GDNF. Since rather low doses of glial cell line-derived neurotrophic factor at nanogram levels appear to saturate these effects, it may be critical to adjust GDNF levels using tightly regulated gene expression systems.
- Subjects :
- Analysis of Variance
Animals
Apomorphine pharmacology
Behavior, Animal
Cell Count methods
Corpus Striatum cytology
Corpus Striatum metabolism
Corpus Striatum transplantation
Disease Models, Animal
Drug Interactions
Female
Green Fluorescent Proteins metabolism
Motor Activity physiology
Neurons drug effects
Neurons metabolism
Psychomotor Performance drug effects
Psychomotor Performance physiology
Rats
Rats, Sprague-Dawley
Recovery of Function drug effects
Recovery of Function physiology
Rotarod Performance Test methods
Transplants
Tyrosine 3-Monooxygenase metabolism
Vesicular Monoamine Transport Proteins metabolism
Cell Transplantation methods
Dopamine metabolism
Glial Cell Line-Derived Neurotrophic Factor administration & dosage
Motor Activity drug effects
Parkinson Disease drug therapy
Parkinson Disease surgery
Subjects
Details
- Language :
- English
- ISSN :
- 0306-4522
- Volume :
- 141
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 16697115
- Full Text :
- https://doi.org/10.1016/j.neuroscience.2006.03.068