Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or glial cell line-derived neurotrophic factor.
The transplantation of fetal mesencephalic cell suspensions into the brain striatal system is an emerging treatment for Parkinson's disease. However, one objection to this procedure is the relatively poor survival of implanted cells. The ability of neurotrophic factors to regulate developmental neuron survival and differentiation suggests they could be used to enhance the success of cerebral grafts. We studied the effects of neurotrophin-3 (NT-3) or glial cell line-derived neurotrophic factor (GDNF) on the survival of dopaminergic neurons from rat fetal ventral mesencephalic cells (FMCs) implanted into the rat striatum. Two conditions were tested: (a) incubation of FMCs in media containing NT-3 and GDNF, prior to grafting, and (b) co-grafting of FMCs with cells engineered to overexpress high levels of NT-3 or GDNF. One week after grafting into the rat striatum, the survival of TH+ neurons was significantly increased by pretreatment of ventral mesencephalic cells with NT-3 or GDNF. Similarly, co-graft of ventral mesencephalic cells with NT-3- or GDNF-overexpressing cells, but not the mock-transfected control cell line, increased the survival of graft-derived dopaminergic neurons. Interestingly, we also found that co-grafting of GDNF-overexpressing cells was less effective than NT-3 at improving the survival of fetal dopaminergic neurons in the grafts, and that only GDNF induced intense TH immunostaining in fibers and nerve endings of the host tissue surrounding the implant. Thus, our results suggest that NT-3, by strongly enhancing survival, and GDNF, by promoting both survival and sprouting, may improve the efficiency of fetal transplants in the treatment of Parkinson's disease.
Espejo
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Departament de Ciències Fisiològiques II, Universitat de Barcelona, Hospitalet del Llobregat, Spain.
Cutillas
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B
Arenas
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Ambrosio
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D016475:3T3 Cells / Q000637:transplantation; D000818:Animals; D016380:Brain Tissue Transplantation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000601:surgery*; D004298:Dopamine / Q000378:metabolism; D016332:Fetal Tissue Transplantation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006085:Graft Survival / Q000187:drug effects; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000601:surgery; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000637:transplantation*; D020933:Neurotrophin 3 / Q000235:genetics / Q000494:pharmacology*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine