Quantitative [18F]Fluorodopa/PET and Histology of Fetal Mesencephalic Dopaminergic Grafts to the Striatum of MPTP-Poisoned Minipigs

• Published in: Cell transplantation Vol. 11; no. 8; pp. 733 - 746
• Main Authors: Dall, Annette Møller, Danielsen, Erik Hvid, Sørensen, Jens Christian, Andersen, Flemming, Møller, Arne, Zimmer, Jens, Gjedde, Albert H., Cumming, Paul, Zimmer, J., Brevig, T., Dall, A. M., Meyer, M., Pedersen, E. B., Gjedde, A., Danielsen, E. H., Cumming, P., Andersen, F., Bender, D., Falborg, L., Gee, A., Gillings, N. M., Hansen, S. B., Hermansen, F., Jørgensen, H. A., Munk, O., Poulsen, P. H., Rodell, A. B., Sakoh, M., Simonsen, C. Z., Smith, D. F., Sørensen, J. C., Østergård, L., Moller, A., Johansen, T. E.
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.11.2002; SAGE Publishing
• Subjects: Animals; Behavior, Animal; Brain Tissue Transplantation; Cell Line; Corpus Striatum - surgery; Dihydroxyphenylalanine - analogs & derivatives; Dopamine - physiology; Fluorine Radioisotopes; Glial Cell Line-Derived Neurotrophic Factor; Graft Survival; Male; Mesencephalon - transplantation; MPTP Poisoning - diagnostic imaging; MPTP Poisoning - pathology; MPTP Poisoning - surgery; Nerve Growth Factors - physiology; Neurons - physiology; Neurons - transplantation; Rats; Swine, Miniature; Tomography, Emission-Computed; Transplantation, Heterologous; Parkinsonism; [18F]Fluorodopa; Stereology; Minipig; MPTP; Grafting; PET; DOPA decarboxylase
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/000000002783985314

The functional restoration of the dopamine innervation of striatum in MPTP-poisoned Göttingen minipigs was assessed for 6 months following grafting of fetal pig mesencephalic neurons. Pigs were assigned to a normal control group and a MPTP-poisoned group, members of which received no further treatment, or which received bilateral grafts to the striatum of tissue blocks harvested from E28 fetal pig mesencephalon with and without immunosuppressive treatment after grafting, or with additional co-grafting with immortalized rat neural cells transfected to produce GDNF. In the baseline condition, and again at 3 and 6 months postsurgery, all animals were subjected to quantitative [18F]fluorodopa PET scans and testing for motor impairment. At the end of 6 months, tyrosine hydroxylase (TH)-containing neurons were counted in the grafts by stereological methods. The MPTP poisoning persistently reduced the magnitude of k3D, the relative activity of DOPA decarboxylase in striatum, by 60%. Grafting restored the rate of [18F]fluorodopa decarboxylation to the normal range, and normalized the scores in motor function. The biochemical and functional recovery was associated with survival of approximately 100,000 TH-positive graft neurons in each hemisphere. Immunosuppression did not impart a greater recovery of [18F]fluorodopa uptake, nor were the number of TH-positive graft neurons or the volumes of the grafts increased in the immunosuppressed group. Contrary to expectation, co-grafting of transfected GDNF-expressing HiB5 cells, a rat-derived neural cell line, tended to impair the survival of the grafts with the lowest values for graft volumes, TH-positive cell numbers, behavioral scores, and relative DOPA decarboxylase activity. From the results we conclude that pig ventral mesencephalic allografts can restore functional dopamine innervation in adult MPTP-lesioned minipigs.