TY - JOUR
T1 - Quantitative [18F]fluorodopa/PET and histology of fetal mesencephalic dopaminergic grafts to the striatum of MPTP-poisoned minipigs.
AU - Dall, Annette Møller
AU - Danielsen, Erik Hvid
AU - Sørensen, Jens Christian
AU - Andersen, Flemming
AU - Møller, Arne
AU - Zimmer, Jens
AU - Gjedde, Albert H
AU - Cumming, Paul
AU - Danish, Neuronal Xenografting Group
AU - Meyer, Morten
N1 - Morten Meyer medlem af DaNeX Study Group
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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 k3(D), 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.
AB - 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 k3(D), 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.
KW - Animals
KW - Behavior, Animal
KW - Brain Tissue Transplantation
KW - Cell Line
KW - Corpus Striatum
KW - Dihydroxyphenylalanine
KW - Dopamine
KW - Fluorine Radioisotopes
KW - Glial Cell Line-Derived Neurotrophic Factor
KW - Graft Survival
KW - MPTP Poisoning
KW - Male
KW - Mesencephalon
KW - Nerve Growth Factors
KW - Neurons
KW - Rats
KW - Swine, Miniature
KW - Tomography, Emission-Computed
KW - Transplantation, Heterologous
U2 - 10.3727/000000002783985314
DO - 10.3727/000000002783985314
M3 - Journal article
C2 - 12588105
SN - 0963-6897
VL - 11
SP - 733
EP - 746
JO - Cell Transplantation
JF - Cell Transplantation
IS - 8
ER -