Parkinson's disease is a progressive debilitating neurodegenerative disorder for which there is no cure. The objective of this research project is to determine if neural grafting can improve the fixed neurological deficits of parkinsonism. The MPTP Parkinson-like syndrome is an excellent model to test surgical techniques for neural transplantation. Two major difficulties with application of neural transplantation are the poor graft survival (5-10 percent in most series) and the relatively poor degree of host reinnervation due to axonal migration of only 1-2 mm. from the graft. We have been able to demonstrate considerably higher survival rates and neuronal transformation when adrenal tissue was co-grafted with Schwann cells which presumably supplied the necessary growth factor(s). We propose to study the use of growth factors to determine whether fetal dopaminergic neurons can be promoted to more successfully survive and more robustly reinnervate the host striatum to produce functional recovery. These experiments should indirectly address the controversy that following transplantation, improvement in parkinsonian symptoms in the MPTP model is due to the reinnervation of the host. Motor activity will be evaluated by clinical examination, computer image analysis of spontaneous caged activity, drug-induced rotation, and performance on learned visual motor fore-limb tasks. The use of standard anatomical assessment, as well as Positron Emission Tomography assessment, should allow an investigation of (a) whether the extent of improvement is dependent upon the degree of dopaminergic reinnervation of the host, (b) whether the dopaminergic reinnervation changes with time paralleling motor improvement, and (c) whether dopaminergic reinnervation can be enhanced through the use of growth factors. Anatomical evaluations will allow not only determination of the survival of dopaminergc neurons, but also the fate of GABAergic neurons which also are concentrated in the ventral mesencephalon. Using a technique we are developing, all grafted cells can be identified. One of the most important questions are how well the noninvasive tests parallel the anatomical studies and correlate correlate with the degree of behavioral improvement. If the severe neurological symptoms of parkinsonism can be improved in this nonhuman primate model, the implications ar extremely important not only for ongoing transplantation clinical trials for parkinsonism, but also suggest possible hope for repair and restoration of neurological deficits following disease or injury.
