Long-term restoration of nigrostriatal system function by implanting GDNF genetically modified fibroblasts in a rat model of Parkinson's disease.
The motor behavior and levels of dopamine and its metabolites in the striatum were studied in rats that received a unilateral injection of 6-OHDA and underwent grafting of rat-derived primary fibroblasts that had been genetically modified to express lacZ and human glial cell line-derived neurotrophic factor (GDNF). Rotation behavior tests were performed each week and striatal levels of DA and its metabolites were measured every 4 weeks after grafting of fibroblasts that expressed lacZ, with or without additional transfection of the GDNF transgene. Rats grafted with GDNF-producing fibroblasts showed a significant improvement in motor behavior as determined by the rotation test, with a less pronounced reduction in the levels of dopamine and its metabolites in the striatum as compared with those in the control animals or brain parts. In addition, there was a lower decrease in the number of TH immunoreactive neurons in the substantia nigra ipsilateral to the lesion in rats with GDNF-producing fibroblasts than in rats with lacZ-expressing fibroblasts. These results support the notion that intracerebral grafting of fibroblasts that express GDNF is a potentially useful therapeutic strategy for treating Parkinson's disease.
Beijing Institute for Neuroscience and Beijing Center for Neural Regeneration and Repairing, Capital University of Medical Sciences, 100054 Beijing, China.
Deyi
D
Duan
Hui
H
Yang
Jingzhong
J
Zhang
Jinlu
J
Zhang
Qunyuan
Q
Xu
D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000637:transplantation*; D015316:Genetic Therapy / Q000379:methods*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D016378:Tissue Transplantation / Q000379:methods*; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine