Implantation of bioactive growth factor-secreting rods enhances fetal dopaminergic graft survival, outgrowth density, and functional recovery in a rat model of Parkinson's disease.
One of the drawbacks with fetal ventral mesencephalic (VM) grafts in Parkinson's disease is the limited outgrowth into the host striatum. In order to enhance graft outgrowth, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were administered by implantation of bioactive rods to the lateral part of the striatum to support grafted fetal VM implanted to the medial portion of the striatum. The polymer-based bioactive rods allow for a local secretion of neurotrophic factors over a time period of approximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta1 (TGFbeta1) were administered using the same technique. Concomitant administration of GDNF and TGFbeta1 was achieved by insertion of one GDNF and one TGFbeta1 rod. This was performed to investigate possible additive effects between GDNF and TGFbeta1. Rotational behavior, outgrowth from and nerve fiber density within the VM graft, and the number of TH-positive cells were studied. Functional compensation by reduction of rotational behavior was significantly enhanced in animals carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreover, the nerve fiber density within the grafts was significantly enhanced by bFGF. Cell counts showed that a significantly higher number of TH-positive neurons was found in grafts treated with bFGF than that found in GDNF-treated grafts. An additive effect of TGFbeta1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neurotrophic factors into the brain, and since bFGF was a potent factor concerning both functional, immunohistochemical and cell survival results, it might be of interest to use bFGF-secreting rods for enhancing the overall outcome of VM grafts into patients suffering from Parkinson's disease.
Törnqvist
N
N
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Björklund
L
L
Almqvist
P
P
Wahlberg
L
L
Strömberg
I
I
D000818:Animals; D002452:Cell Count / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004343:Drug Implants; D004359:Drug Therapy, Combination; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects*; D006133:Growth Substances / Q000008:administration & dosage*; D008636:Mesencephalon / Q000187:drug effects / Q000637:transplantation; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D011145:Polyvinyls / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000008:administration & dosage; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D003692:Delayed-Action Preparations; D004343:Drug Implants; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D006133:Growth Substances; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011145:Polyvinyls; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; C016438:ethylenevinylacetate copolymer; D004815:Epidermal Growth Factor; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase