Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections.
The effects of delivering GDNF via an adenoviral vector (AdGDNF) 1 week after lesioning dopaminergic neurons in the rat substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) were examined. Rats were unilaterally lesioned by injection of 6-OHDA into the striatum, resulting in progressive degeneration of dopaminergic neurons in the SN. One week later, when substantial damage had already occurred, AdGDNF or a control vector harboring beta-galactosidase (AdLacZ) was injected into either the striatum or SN (3.2 x 10(7) PFU/microl in 2 microl). Rats were examined behaviorally with the amphetamine-induced rotation test and for forelimb use for weight-bearing movements. On day 30 postlesion, the extent of nigrostriatal tract degeneration was determined by injecting a retrograde tracer (FluoroGold) bilaterally into the lesioned striatum. Five days later, rats were sacrificed within 2 h of amphetamine injection to examine amphetamine-induced Fos expression in the striatum, a measure of dopaminergic-dependent function in target neurons. AdGDNF injection in the SN rescued dopaminergic neurons in the SN and increased the number of dopaminergic neurons that maintained a connection to the striatum, compared to rats injected with AdLacZ. Further support that these spared SN cells maintained functional connections to the striatum was evidenced by increased Fos expression in striatal target neurons and a decrease in amphetamine-induced rotation. In contrast to the effects observed in rats injected with AdGDNF in the SN, rats injected with AdGDNF in the striatum did not exhibit significant ameliorative effects. This study demonstrates that experimentally increasing levels of GDNF biosynthesis near the dopaminergic neuronal soma is effective in protecting the survival of these neurons and their function even when therapy is begun after 6-OHDA-induced degeneration has commenced. Thus, GDNF gene therapy may ameliorate the consequences of Parkinson's disease through rescuing compromised dopaminergic neurons.
Kozlowski
D A
DA
Department of Pediatrics, Children's Memorial Institute for Education and Research, Chicago, Illinois 60614, USA.
Connor
B
B
Tillerson
J L
JL
Schallert
T
T
Bohn
M C
MC
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005456:Fluorescent Dyes; D015316:Genetic Therapy / Q000379:methods*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000627:therapeutic use*; D009434:Neural Pathways / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020127:Recovery of Function / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D005456:Fluorescent Dyes; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine