Studies in rodents and nonhuman primates suggest that up to 95% of grafted dopamine (DA) neurons die within the first week after implantation into the striatum, a possible contributor to poor clinical outcome in studies to date. In addition, poor survival of grafted cells appears to be exaggerated when cells are implanted into an elderly host. Multiple insults associated with the transplant procedure and early post-graft interval could render grafted cells susceptible to death, including mechanical trauma, hypoxia, oxidative stress, and neurotrophic factor withdrawal. Despite these problems, the identification of cell death mechanisms operating in DA grafts, and their probable triggers, provides access to cogent interventions to limit death of grafted neurons. This project aims to investigate four interventions that may limit death of grafted neurons, optimizing the potential for DA replacement and recovery of function: 1) reducing the apoptosis triggered by dissection and preparation of the tissue for implantation, termed """"""""anoikis"""""""", via treatment with the cell adhesion factors L1 antibody and tenascin, and, 2) utilizing treatment with the lazaroid tirilazad mesylate and melatonin to reduce oxidant stress, 3) reducing hypoxia/ischemia by accelerating neovascularization of grafts using treatment with vascular endothelial growth factor (VEGF), 4) stimulating the DA phenotype of grafted cells by exposure to cyclic AMP. All interventions proposed have yielded significant graft augmentation in rodent experiments. In the present application, each intervention will be tested for functional efficacy in young adult MPTP-treated St. Kitts green monkeys. Optimally aged fetal mesencephalic tissue, with varying treatments, will be implanted into the striatum, and quantitative behavioral measurements will assess functional outcome, correlated with histological and biochemical evidence of more extensive grafts. A final experiment will combine treatments proven individually to augment graft function in young adult monkeys, and compare the functional outcome of this combination therapy in young adult and aged MPTP-treated monkeys. Successful methods for augmentation of grafted cell survival and growth may improve transplantation results and be applicable to stem cells or other cell-based therapies for Parkinson's disease.
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