The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted toa minipig model of Parkinson's disease: Preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers

A multicenter study is under way to investigate the efficacy of allograftin g of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be estab lished by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Gottingen minipigs. We are now using positron emission tomogr aphy (PET) methods for testing the physiological responses to MPTP intoxica tion and the time course of the response to several treatment strategies. W e now report preliminary results obtained in 11 pigs employed in the initia l phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxicat ion followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression acid co-grafting of immoratize d HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (approximate to 2 ng GDNF/h/10(5) cells). MPTP w as administered (1 mg/kg/day, SC) for 7-10 days until the pigs had develope d mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings, After the First series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 da ys) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-b ased stereotactic techniques. Immunosuppression of some animals with cyclos porin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last sca ns, pigs were killed and the blains were perfused for unbiased stereologica l examination of cytological and histochemical markers in striatum and subs tantial nigra. The behavioral impairment of the animals (the "Parkinson's s core") had been evaluated throughout the 8-month period. Kinetic analysis o f the first set of PET scans has indicated th;lt the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in stri atum of the mildly parkinsonian pigs. The rate of association of [C-11]NS-2 214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [C-11 ]raclopride to the dopamine D-2-like receptors in striatum of the MPTP-into xicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially dene rvated pig striatum.