Effects of GDNF pretreatment on function and survival of transplanted fetal ventral mesencephalic cells in the 6-OHDA rat model of Parkinson's disease.
Transplantation of fetal dopaminergic (DA) neurons offers an experimental therapy for Parkinson's disease (PD). The low availability and the poor survival and integration of transplanted cells in the host brain are major obstacles in this approach. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with growth- and survival-promoting capabilities for developing DA neurons. In the present study, we examined whether pretreatment of ventral mesencephalic (VM) free-floating roller tube (FFRT) cultures with GDNF would improve graft survival and function. For that purpose organotypic cultures of E14 rat VM were grown for 2, 4 or 8 days in the absence (control) or presence of GDNF [10 ng/ml] and transplanted into the striatum of 6-hydroxydopamine-lesioned rats. While all groups of rats showed a significant reduction in d-amphetamine-induced rotations at 6 weeks posttransplantation a significantly improved graft function was observed only in the days in vitro (DIV) 4 GDNF pretreated group compared to the control group. In addition, no statistical significant differences between groups were found in the number of surviving tyrosine hydroxylase-immunoreactive (TH-ir) neurons assessed at 9 weeks posttransplantation. However, a tendency for higher TH-ir fiber outgrowth from the transplants in the GDNF pretreated groups as compared to corresponding controls was observed. Furthermore, GDNF pretreatment showed a tendency for a higher number of GIRK2 positive neurons in the grafts. In sum, our findings demonstrate that GDNF pretreatment was not disadvantageous for transplants of embryonic rat VM with the FFRT culture technique but only marginally improved graft survival and function.
Andereggen
Lukas
L
Department of Neurosurgery, University of Bern, Inselspital, CH-3010 Berne, Switzerland.
Meyer
Morten
M
Guzman
Raphael
R
Ducray
Angélique D
AD
Widmer
Hans Rudolf
HR
D000661:Amphetamine / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D004195:Disease Models, Animal; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000627:therapeutic use*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D051100:Glial Cell Line-Derived Neurotrophic Factor; C497070:Kcnj6 protein, rat; D018696:Neuroprotective Agents; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase