Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson's disease.
Glial cell-line derived neurotrophic factor (GDNF) is a good candidate agent for restoring functional reinnervation and/or neuroprotection of dopamine (DA) nigrostriatal system and thus for the treatment of Parkinson's disease (PD). Viral delivery is currently the most likely in vivo strategy for delivery of the therapeutic protein into the brain for treatment of neurological diseases. However, one of the important unresolved issues for this strategy is the threshold number of DA nigral neurons and/or of striatal DA terminals necessary for optimal benefit from GDNF therapy. In this study, we examined the intrastriatal neurotrophic effects of long-term GDNF delivery using a lentiviral vector in a new rat model of early PD. Lenti-GDNF was injected into the striatum 4 weeks after partial substantia nigra pars compacta 6-hydroxydopamine-induced lesion. Striatal denervation was evaluated by assessing tyrosine hydroxylase-positive DA fiber density and corroborated by testing motor deficit by means of a staircase test. GDNF treatment restored complete striatal DA innervation in the previously denervated area and this was associated with significant behavioral improvements.
Brizard
Mara
M
Laboratoire de Génétique Moléculaire des Processus Neurodégénératifs et de la Neurotransmission-Unité Mixte de Recherche, bâtiment CERVI, 83 boulevard de l'Hôpital, 75013 PARIS, France.
Carcenac
Carole
C
Bemelmans
Alexis-Pierre
AP
Feuerstein
Claude
C
Mallet
Jacques
J
Savasta
Marc
M
D000818:Animals; D003342:Corpus Striatum / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D009068:Movement; D009410:Nerve Degeneration / Q000503:physiopathology / Q000628:therapy; D009416:Nerve Regeneration; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000503:physiopathology / Q000628:therapy*; D017729:Presynaptic Terminals / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013565:Sympatholytics / Q000633:toxicity
D051100:Glial Cell Line-Derived Neurotrophic Factor; D013565:Sympatholytics; D016627:Oxidopamine; D004298:Dopamine