Dissociation between short-term increased graft survival and long-term functional improvements in Parkinsonian rats overexpressing glial cell line-derived neurotrophic factor.
The present study was designed to analyse whether continuous overexpression of glial cell line-derived neurotrophic factor (GDNF) in the striatum by a recombinant lentiviral vector can provide improved cell survival and additional long-term functional benefits after transplantation of fetal ventral mesencephalic cells in Parkinsonian rats. A four-site intrastriatal 6-hydroxydopamine lesion resulted in an 80-90% depletion of nigral dopamine cells and striatal fiber innervation, leading to stable motor impairments. Histological analysis performed at 4 weeks after grafting into the GDNF-overexpressing striatum revealed a twofold increase in the number of surviving tyrosine hydroxylase (TH)-positive cells, as compared with grafts placed in control (green fluorescent protein-overexpressing) animals. However, in animals that were allowed to survive for 6 months, the numbers of surviving TH-positive cells in the grafts were equal in both groups, suggesting that the cells initially protected at 4 weeks failed to survive despite the continued presence of GDNF. Although cell survival was similar in both grafted groups, the TH-positive fiber innervation density was lower in the GDNF-treated grafted animals (30% of normal) compared with animals with control grafts (55% of normal). The vesicular monoamine transporter-2-positive fiber density in the striatum, by contrast, was equal in both groups, suggesting that long-term GDNF overexpression induced a selective down-regulation of TH in the grafted dopamine neurons. Behavioral analysis in the long-term grafted animals showed that the control grafted animals improved their performance in spontaneous motor behaviors to approximately 50% of normal, whereas the GDNF treatment did not provide any additional recovery.
Georgievska
Biljana
B
Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, BMC A11, 22184, Lund, Sweden. Biljana.Georgievska@mphy.lu.se
Carlsson
Thomas
T
Lacar
Benjamin
B
Winkler
Christian
C
Kirik
Deniz
D
D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D017690:Cell Transplantation / Q000379:methods*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology / Q000637:transplantation; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006085:Graft Survival / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology / Q000637:transplantation; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000628:therapy*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology*; D045442:Rotarod Performance Test / Q000379:methods; D013238:Stereotaxic Techniques; D013239:Stereotyped Behavior / Q000187:drug effects / Q000941:ethics / Q000502:physiology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D034941:Upper Extremity / Q000503:physiopathology; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D018663:Adrenergic Agents; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009414:Nerve Growth Factors; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase