title: Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson's disease.
abstract: Transplantation of embryonic dopamine (DA) neurons is being studied as an experimental replacement therapy for the DA-deficiency characteristic of Parkinson's disease. Some studies suggest that one of the limitations of this approach is that intrastriatal placement of implants fails to consistently restore completely normal movement. One potential cause of this suboptimal therapeutic outcome is that changes in the neural activity of several structures in the basal ganglia circuitry resulting from striatal DA depletion is not adequately normalized by graft-derived DA replacement in striatum alone. In the present study, we assessed the feasibility of grafting embryonic DA neurons into the substantia nigra (SN) of adult parkinsonian monkeys as an approach to restoration of the DA modulation of striatal-nigral afferents that is lost after degeneration of SN neurons. Sixteen St. Kitts African green monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) received implants of embryonic monkey ventral mesencephalon (VM), or sham implants, aimed at the rostral SN. At 6 months after grafting, staining for tyrosine hydroxylase (TH) indicated that grafted DA neurons survived at this site, albeit often in reduced numbers compared with VM grafts to striatum. Grafted neurons extended neurites into the parenchyma of the SN, but there was no evidence of lengthy extension of graft-derived neurites rostrally along the trajectory of the mesostriatal fiber system. A region-specific, modest increase in DA levels and TH-positive fiber density in the ventral-medial putamen was detected, accompanied by modest but significant decreases in parkinsonian behaviors at 5-6 months after grafting. Our findings support the view that grafting embryonic tissue to the SN is a feasible procedure in nonhuman primates that provides a modest but detectable benefit of its own. These results encourage the further development of multiple-target grafting strategies as a means of restoring modulation of anatomically widespread basal ganglia structures relevant to treatment of Parkinson's disease.
authors.affiliation: Department of Neurological Sciences, Research Center for Brain Repair, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA. tcollier@rush.edu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Collier
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Sortwell
authors.forename: John D
authors.initials: JD
authors.lastname: Elsworth
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
authors.forename: Robert H
authors.initials: RH
authors.lastname: Roth
authors.forename: John R
authors.initials: JR
authors.lastname: Sladek
authors.forename: D Eugene
authors.initials: DE
authors.lastname: Redmond
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D016380:Brain Tissue Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000502:physiology; D002522:Chlorocebus aethiops / Q000033:anatomy & histology / Q000601:surgery*; D004298:Dopamine / Q000378:metabolism*; D006085:Graft Survival / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020127:Recovery of Function / Q000502:physiology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013378:Substantia Nigra / Q000196:embryology / Q000601:surgery* / Q000637:transplantation*; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid