Neuronal transplantation in rodents has become a major focus of neuroscience research. It holds promise for clinical application, particularly to degenerative diseases of the aging nervous system such as parkinsonism. Despite clear recognition that primates differ from rodents in neuroanatomey, neurochemistry, and behavior associated with the neostriatum, insufficient studies have been conducted in primates to establish effective, safe and reliable techniques. Reasons for this slow pace include lack of a convenient, quantifiable, reliable model in which to test the various parameters of transplantation techniques in primates, and the logistical difficulties of assembling the primate research resources necessary for systematic studies. We will apply a newly developed model that meets these requirements. Dopaminergic cells of Macaca fascicularis are destroyed by unilateral neurotoxin injections directly into the substantia nigra, resulting in a hemiparkinsonian syndrome. Dopamine cells, transplanted from a macaque fetus into the corpus striatum, measurably reverse this syndrome. Eighty-four monkeys will be studied, over five years, to answer basic and clinical questions that should be addressed in nonhuman primates before transplants are used in humans: (1) What are the best injection parameters (interval between lesion and transplant, fetal donor age, neuronal concentration, cell suspension method, and injection rate and volume) for fetal mesencephalic cell transplants? (2) Can removal of immunogenic cells and concentration of dopamine neurons, by cell-sorting of suspensions prior to transplantation, improve transplant success? (3) Can adrenal tissue be used as a source of dopaminergic cells in primates? (4) What sites in dopamine terminal areas should be given transplants to optimize clinical effects? (5) Can a critical problem for human transplantation, namely the safe distribution of transplant material throughout a very large striatum, be met by an innovative method for injecting neuronal suspensions with minimal cortical damage? (6) Will behavior restored by transplants remain stable or fluctuate over time? (7) Will concurrent treatment with cyclosporin, L-DOPA, or nerve growth factor influence transplant success? (8) Does aging of the host influence the effectiveness of transplants in primates? The answers to these questions will be significant for potential transplant treatment of a variety of neurological disorders, particularly degenerative diseases associated with aging.
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