BRAIN TRANSPLANT TREATMENT FOR PARKINSONIANS

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Transplantation of rat fetal substantial nigra into rat striatum denervated of dopamine input has been successful at restoring some motor behaviors. The new discovery that primates can be made Parkinsonian with the drug methylphenyltetrahydropyridine (MPTP) has made it possible to extend fetal transplant therapy to the primate. We will train male Bonnet (Macaca radiata) monkeys to pull a lever with either the left or right hands for a food reward. A light cue will be used to signal which hand is to be used for the reward. After stable performance is achieved, animals will be made Parkinsonian with daily injections of MPTP 0.5 mg/kg i.m. An average of 4 to 5 injections will be required. Animals will be maintained during the acute intoxication syndrome with tube feedings if necessary. In animals spontaneously recovering from the lesion, additional courses of MPTP will be given until a significant and stable lesion results. Once stable performance is achieved (3-4 months after the induction of the syndrome), animals will be transplanted with fetal tissue from the ventral mesencephalon of fetal Bonnet monkeys embryonic age 35-40 days. Injections of minced tissue will be made unilaterally into head of caudate and into putamen at multiple sites. Animals will be tested at twice weekly intervals for improved motor performance. We expect that there will be greater improvement in motor performance in the limb contralateral to the transplant site occurring 3 to 4 months after the transplant. Animals will be sacrificed 6 months after transplant and brain studied with tyrosine hydroxylase immunocytochemical techniques for evidence of transplant survival. In subsequent experiments, animals will be transplanted only into caudate or putamen to see which site is more important for motor improvement. Delayed match to sample tests will be done to assess higher cognitive skills in these later experiments. The outcome of these experiments will directly predict the value of fetal transplate in human patients with Parkinson's disease.