Functional improvement with low-dose dopaminergic grafts in hemiparkinsonian rats.
OBJECTIVE
The beneficial functional effects of neural transplantation in Parkinson's disease are often directly attributed to the number of surviving dopaminergic cells within a graft. However, recent clinical trials of fetal neural transplantation suggest that a high number of dopaminergic cells may induce serious side effects. In this study, we explored the ability of low-dose dopaminergic grafts to produce functional benefits in the 6-hydroxydopamine rodent model of Parkinson's disease over a long period of observation.


METHODS
Twelve rats received either 50,000 or 400,000 fetal ventral mesencephalic cells implanted into the striatum. Rotational behavior was assessed after the lesion and at 3, 6, 9, and 12 weeks after transplantation. Twelve weeks after transplantation, animals were perfused, and microtome sections were stained for tyrosine hydroxylase, glial fibrillary acidic protein, heat-shock protein 27, and vimentin.


RESULTS
The low-dose group had a three-fold increase in tyrosine hydroxylase-positive cell survival rate compared with the high-dose group rate. The low-dose group also had a mean cell diameter significantly higher than the high-dose group. There was no significant difference between groups in fiber density; however, a higher percentage of longer fibers was encountered in the low-dose group. The low-dose group had a lower degree of trauma in the striatum, as assessed by optical density scores from glial fibrillary acidic protein, heat-shock protein 27, and vimentin staining. There was significant improvement in rotational behavior in the high-dose group at 3 weeks after transplantation, whereas the rotational behavior normalized in the low-dose group at 6 weeks after grafting. There was no significant difference in rotational behavior scores between groups at 6 weeks after grafting.


CONCLUSIONS
This study demonstrates that over time, a low-dose dopaminergic graft has the capability of eliciting the same functional effect as a high-dose graft. Furthermore, low-dose grafts may increase graft survival, fiber outgrowth, and dopamine production and decrease trauma to the brain.
Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Lynsey E
LE
Bartlett
Damaso
D
Sadi
Matthew
M
Lewington
Ivar
I
Mendez
D000818:Animals; D016380:Brain Tissue Transplantation / Q000473:pathology / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D004298:Dopamine / Q000008:administration & dosage* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016332:Fetal Tissue Transplantation / Q000473:pathology / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006360:Heat-Shock Proteins / Q000032:analysis; D008636:Mesencephalon / Q000196:embryology* / Q000637:transplantation*; D008856:Microscopy, Fluorescence; D009412:Nerve Fibers / Q000473:pathology / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000502:physiology; D014746:Vimentin / Q000032:analysis
D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; D014746:Vimentin; D016627:Oxidopamine; D004298:Dopamine