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-derived neurotrophic factor (GDNF) protects dopaminergic (DA) neurons in the substantia nigra (SN) of young rats. As Parkinson's disease occurs primarily in aged populations, we examined whether chronic biosynthesis of GDNF, achieved by adenovirus-mediated delivery of a GDNF gene (AdGDNF), can protect DA neurons and improve DA-dependent behavioral function in aged (20 months) rats with progressive 6-OHDA lesions of the nigrostriatal projection. Furthermore, the differential effects of injecting AdGDNF either near DA cell bodies in the SN or at DA terminals in the striatum were compared. AdGDNF or control vector was injected unilaterally into either the striatum or SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the same side as the vector injection. AdGDNF injection into either the striatum or SN significantly reduced the loss of FG labelled DA neurons 5 weeks after lesion (P </= 0.05). However, only striatal injections 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 striatal Fos expression. These results demonstrate that increased levels of striatal, but not nigral, GDNF biosynthesis prevents DA neuronal loss and protects DA terminals from 6-OHDA-induced damage, thereby maintaining DA function in the aged rat.
Connor
B
B
Department of Psychology, University of Texas, Austin, TX, USA.
Kozlowski
D A
DA
Schallert
T
T
Tillerson
J L
JL
Davidson
B L
BL
Bohn
M C
MC
D000256:Adenoviridae / Q000235:genetics; D000661:Amphetamine; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents; D015870:Gene Expression; D018014:Gene Transfer Techniques; D016762:Genes, fos; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007276:Injections, Intraventricular; D008297:Male; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018696:Neuroprotective Agents; D010300:Parkinson Disease / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine