Differential effects of glial cell line-derived neurotrophic factor (GDNF)in the striatum and substantia nigra of the aged Parkinsonian rat

Injection of an adenoviral (Ad) vector encoding human glial cell line-deriv ed neurotrophic factor (GDNF) protects dopaminergic (DA) neurons in the sub stantia nigra (SN) of young rats. As Parkinson's disease occurs primarily i n aged populations, we examined whether chronic biosynthesis of GDNF, achie ved by adenovirus-mediated delivery of a GDNF gene (AdGDNF), can prefect DA neurons and improve DA-dependent behavioral function in aged (20 months) r ats with progressive 6-OHDA lesions of the nigrostriatal projection. Furthe rmore, the differential effects of injecting AdGDNF either near DA cell bod ies in the SN or at DA terminals in the striatum were compared. AdGDNF or c ontrol vector was injected unilaterally into either the striatum or SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA o n the same side as the vector injection. AdGDNF injection into either the s triatum or SN significantly reduced the loss of FG labelled DA neurons 5 we eks after lesion (P less than or equal to 0.05). However, only striatal inj ections of AdGDNF protected against the development of behavioral deficits characteristic of unilateral DA depletion. Striatal AdGDNF injections also reduced tyrosine hydroxylase fiber loss and increased amphetamine-induced s triatal Fos expression. These results demonstrate that increased levels of striatal, but not nigral, GDNF biosynthesis prevents DA neuronal loss and p rotects DA terminals from 6-OHDA-induced damage, thereby maintaining DA fun ction in the aged rat.