Glial cell line-derived neurotrophic factor increases survival, growth and function of intrastriatal fetal nigral dopaminergic grafts.
The ability of transplants of fetal nigral neurons to reverse symptoms in patients with Parkinson's disease is, at least in part, limited by the poor survival of the grafted dopaminergic neurons and the restricted host reinnervation from the graft. Here, we report that glial cell line-derived neurotrophic factor, a novel trophic factor for developing dopaminergic neurons, can increase survival and fibre outgrowth of fetal nigral dopaminergic neurons, and stimulate graft-induced functional recovery after transplantation in a rat model of Parkinson's disease. Injections of rat glial cell line-derived neurotrophic factor adjacent to the graft enhanced graft function, resulting in complete compensation of amphetamine-induced turning behaviour already by two weeks postgrafting as opposed to four weeks in the control group. The total number of surviving tyrosine hydroxylase-positive neurons was about two-fold greater in the glial cell line-derived neurotrophic factor-treated animals compared to the vehicle-injected controls, and the density of tyrosine hydroxylase-positive fibres was found to be increased both in the host striatum (from 37.6 +/- 8.3% to 105.5 +/- 9.7% of intact striatum) as well as inside the graft (55% increase). Moreover, in animals treated with glial cell line-derived neurotrophic factor, the outgrowth of tyrosine hydroxylase-positive fibres was mostly directed towards the injection site. These findings show that supply of exogenous glial cell line-derived neurotrophic factor to the transplantation site improves survival, growth and function of transplanted fetal nigral dopaminergic neurons in the rat Parkinson model.
Rosenblad
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Department of Physiology and Neuroscience, Wallenberg Neuroscience Center, University of Lund, Sweden.
Martinez-Serrano
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Björklund
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D000818:Animals; D016380:Brain Tissue Transplantation / Q000473:pathology / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D016332:Fetal Tissue Transplantation / Q000473:pathology / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006085:Graft Survival / Q000187:drug effects*; D009412:Nerve Fibers / Q000502:physiology / Q000648:ultrastructure; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000601:surgery; D051381:Rats; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000096:biosynthesis
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine