GDNF partially protects grafted fetal dopaminergic neurons against 6-hydroxydopamine neurotoxicity.
Rats were given unilateral 6-hydroxydopamine (6-OHDA) lesions and subsequently received transplants of fetal ventral mesencephalic tissue into the denervated striatum. Four weeks later transplanted animals were tested for graft-mediated reduction of amphetamine-induced rotational behavior. Subsequently, transplanted animals received an intrastriatal injection of either GDNF (10 microg) or citrate buffer into a site lateral to the transplant, and then 6 h later received an injection of either 4.0 microg of 6-OHDA, 8.0 microg of 6-OHDA, or vehicle using the same stereotaxic coordinates that were used for the GDNF/citrate buffer injection. Animals were re-tested for amphetamine-induced rotational behavior 2 weeks later. Histological analysis revealed a significant reduction in the number of cell bodies immunostained for tyrosine hydroxylase (TH+) within the transplant for those animals pretreated with an intrastriatal injection of citrate buffer and subsequently given either dose of 6-OHDA. Transplanted animals pretreated with GDNF and subsequently administered 8.0 microg of 6-OHDA showed a significant reduction of TH+ neurons within the transplant compared to controls, however TH+ cell counts for this group remained significantly higher than the TH+ cell counts for the group of animals receiving the same dose of 6-OHDA but pretreated with citrate buffer. GDNF pretreatment completely protected TH+ cell bodies against 4.0 microg of 6-OHDA. Rotational scores indicated that GDNF provided only partial protection against 6-OHDA neurotoxicity in terms of transplant function. For both groups of transplanted animals receiving GDNF pretreatment and 6-OHDA injections, amphetamine-induced rotational scores dropped below the scores for animals pretreated with citrate buffer but remained significantly higher than the scores for transplanted animals that were not injected with 6-OHDA. Both histological and behavioral measures indicate GDNF partially protects integrated transplants against neurotoxic insult.
Yurek
D M
DM
Department of Surgery/Neurosurgery, University of Kentucky College of Medicine, Health Sciences Research Building, 800 Rose Street, Lexington, KY 40536, USA. dyure00@pop.uky.edu
Fletcher-Turner
A
A
D000818:Animals; D016380:Brain Tissue Transplantation; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology; D016332:Fetal Tissue Transplantation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008297:Male; D017072:Neostriatum / Q000601:surgery; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000637:transplantation*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000633:toxicity
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013565:Sympatholytics; D016627:Oxidopamine; D004298:Dopamine