Fibroblast growth factor-2-producing fibroblasts protect the nigrostriatal dopaminergic system from 6-hydroxydopamine.
We tested the hypothesis that fibroblasts, which had been genetically engineered to produce fibroblast growth factor-2 (FGF-2), can protect nigrostriatal dopaminergic neurons. Three groups of rats received either a burr hole only (n=5) or implantation of fibroblasts, which had been genetically engineered to produce beta-galactosidase (beta-gal) (n=8) or FGF-2 (n=8), at two sites in the right striatum. Two weeks later, the animals received an injection of 25 microg of 6-hydroxydopamine hydrobromide (6-OHDA) midway between the two implant sites. The group that received FGF-2-fibroblasts had significantly fewer apomorphine-induced rotations than the groups that received a burr hole only or beta-gal-fibroblasts at weeks 2 and 3 following lesioning with 6-OHDA. Testing for amphetamine-induced rotation revealed a mild reduction in rotation in the beta-gal-fibroblast group compared to the burr hole only group, but a striking attenuation of amphetamine-induced rotation in the FGF-2-fibroblast group. There was also preservation of TH-IR neurons on the lesioned side relative to both control groups. The size of the grafts and the gliosis surrounding the injection sites did not differ between the FGF-2-fibroblast and beta-gal-fibroblast groups. To further characterize the production of FGF-2 by the FGF-2-fibroblasts, we implanted FGF-2-fibroblasts and beta-gal-fibroblast into the striatum of rats but did not lesion the animals with 6-OHDA. The animals were then sacrificed at 1, 2 and 5 weeks following implantation. Prior to implantation the FGF-2 fibroblasts contained 148 ng/mg of FGF-2-immunoreactive (FGF-2-IR) material per mg of protein of cell lysate. After implantation FGF-2-IR material was noted in the grafts of FGF-2-fibroblasts, most conspicuously at 1 and 2 weeks following implantation. We also noted FGF-2-IR material in the nuclei of reactive astrocytes adjacent to the implants, and OX-42-immunoreactive (OX-42-IR) cells adjacent and occasionally within the implants. Our work indicates that fibroblasts genetically engineered to produce FGF-2 and implanted in the striatum can protect the nigrostriatal dopaminergic system and may be useful in the treatment of Parkinson's disease.
Shults
C W
CW
Neurology Service, Veterans Affairs San Diego Healthcare System, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. cwshults@vapop.ucsd.edu
Ray
J
J
Tsuboi
K
K
Gage
F H
FH
D018663:Adrenergic Agents; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000637:transplantation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D005347:Fibroblasts / Q000378:metabolism* / Q000637:transplantation; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D020955:Striatonigral Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism* / Q000637:transplantation; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D018663:Adrenergic Agents; D016222:Fibroblast Growth Factor 2; D016627:Oxidopamine; D001616:beta-Galactosidase