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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-E (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Redmond Jr, D Eugene; McEntire, Caleb R S; Kingsbery, Joseph P et al. (2013) Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced nonhuman primate Parkinson's model. Mol Ther 21:2160-8
Redmond Jr, D Eugene; Evans, Lawrence (2012) Determination of fetal age by ultrasonography in St. Kitts green monkeys. Am J Primatol 74:433-41
Redmond Jr, D Eugene (2012) Using monkeys to understand and cure Parkinson disease. Hastings Cent Rep Suppl:S7-S11
DeMartelly, Victoria; Hurley, Patrick; Lawrence, Mathew et al. (2012) Comparison of fresh to fixed weights of the vervet monkey (Chlorocebus sabaeus) placenta and its relation to gestational age. J Med Primatol 41:158-62
Morrow, B A; Roth, R H; Redmond Jr, D E et al. (2012) Susceptibility to a parkinsonian toxin varies during primate development. Exp Neurol 235:273-81
Bloch, Jocelyne; Kaeser, Mélanie; Sadeghi, Yalda et al. (2011) Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. J Comp Neurol 519:775-89
Hurley, P J; Elsworth, J D; Whittaker, M C et al. (2011) Aged monkeys as a partial model for Parkinson's disease. Pharmacol Biochem Behav 99:324-32
Morrow, B A; Roth, R H; Redmond, D E et al. (2011) Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease. Neuroscience 189:277-85
Redmond Jr, Donald Eugene; Weiss, Stephanie; Elsworth, John D et al. (2010) Cellular repair in the parkinsonian nonhuman primate brain. Rejuvenation Res 13:188-94
Markakis, Eleni A; Vives, Kenneth P; Bober, Jeremy et al. (2010) Comparative transduction efficiency of AAV vector serotypes 1-6 in the substantia nigra and striatum of the primate brain. Mol Ther 18:588-93

Showing the most recent 10 out of 16 publications