Parkinson's disease (PD) is a progressive debilitating neurodegenerative disorder for which there is no cure. The objective of this research project is to determine if central nervous system (CNS) grafting can improve the fixed neurological symptoms of parkinsonism. The MPTP-induced parkinson-like syndrome is an excellent model. to test surgical techniques for CNS transplantation. Our previous investigations have demonstrated the potential for correcting these Parkinson-like movement abnormalities using either adrenal medullary and sural nerve co-grafts or fetal ventral mesencephalon cell suspensions in the rhesus monkey (Macaca mulatta). The goal of this research is to determine the best tissue for CNS transplantation. The quantification of behavioral recovery of motor deficits will be the key determinant of graft success. Behavioral assessment of motor activity is evaluated by clinical examination, computerized image analysis of spontaneous cage activity, drug-induced rotation, and performance on a learned visual-motor forelimb task. Quantification of motor activity , especially speed of movement, provides an index of the severity of bradykinesia - the most debilitating symptom of parkinsonism. Each monkey will be tested prior to the administration of MPTP, after stabilization of the Parkinson-like state, and postoperatively, thus allowing each monkey to serve as its own control. Anatomical assessment permits comparison of surgical treatment groups by quantification of loss of dopaminergic cells in the substantia nigra determined by tyrosine hydroxylase immunoreactivity. Graft survival is evaluated by counting cells which are immunocytochemically reactive for tyrosine hydroxylase, dopamine-B-hydroxylase, or chromagranin A. Biochemical assessment is performed by serial measurements of dopamine metabolites in the CSF, and by measurement of tissue concentrations of dopamine and its metabolites as well as tyrosine hydroxylase synthetic activity in the neostriatum and graft. The important question is not only which tissue is best, but also how well it corrects the Parkinson symptoms. If the severe neurologic deficits can be successfully improved in nonhuman primates with this' Parkinson-like syndrome, the implications are extremely important not only for the potential clinical treatment of parkinsonism but also for the possible repair and restoration of CNS deficits following disease or injury.
