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

被引:48
作者
Danielsen, EH
Cumming, P
Andersen, F
Bender, D
Brevig, T
Falborg, L
Gee, A
Gillings, NM
Hansen, SB
Hermansen, F
Johansen, J
Johansen, TE
Dahl-Jorgensen, A
Jorgensen, HA
Meyer, M
Munk, O
Pedersen, EB
Poulsen, PH
Rodell, AB
Sakoh, M
Simonsen, CZ
Smith, DF
Sorensen, JC
Ostergård, L
Zimmer, J
Gjedde, A
Moller, A
机构
[1] Aarhus Univ Hosp, PET Ctr, DK-8000 Aarhus C, Denmark
[2] Aarhus Univ Hosp, Dept Neuroradiol, DK-8000 Aarhus C, Denmark
[3] Aarhus Univ Hosp, Dept Neurosurg, DK-8000 Aarhus C, Denmark
[4] Aarhus Univ Hosp, Dept Neuroanaesthesia, DK-8000 Aarhus C, Denmark
[5] Aarhus Univ, Hosp Psychiat, Dept Biol Psychiat, DK-8000 Aarhus C, Denmark
[6] Odense Univ, Univ So Denmark, Dept Anat & Neurobiol, DK-5230 Odense M, Denmark
[7] Neuro Search, Glostrup, Denmark
关键词
Parkinson's disease; animal models; allografts; positron emission tomography (PET);
D O I
10.1177/096368970000900210
中图分类号
Q813 [细胞工程];
学科分类号
摘要
A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Gottingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial 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 intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression acid co-grafting of immoratized 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 was administered (1 mg/kg/day, SC) for 7-10 days until the pigs had developed 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 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the blains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the "Parkinson's score") had been evaluated throughout the 8-month period. Kinetic analysis of 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 striatum of the mildly parkinsonian pigs. The rate of association of [C-11]NS-2214 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-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.
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收藏
页码:247 / 259
页数:13
相关论文
共 60 条
[31]   XENOGRAFTING OF FETAL PIG VENTRAL MESENCEPHALON CORRECTS MOTOR ASYMMETRY IN THE RAT MODEL OF PARKINSONS-DISEASE [J].
HUFFAKER, TK ;
BOSS, BD ;
MORGAN, AS ;
NEFF, NT ;
STRECKER, RE ;
SPENCE, MS ;
MIAO, R .
EXPERIMENTAL BRAIN RESEARCH, 1989, 77 (02) :329-336
[32]   Benefits and risks of hosting animal cells in the human brain [J].
Isacson, O ;
Breakefield, XO .
NATURE MEDICINE, 1997, 3 (09) :964-969
[33]   STRIATAL 3,4-DIHYDROXYPHENYLALANINE DECARBOXYLASE IN AGING - DISPARITY BETWEEN POSTMORTEM AND POSITRON EMISSION TOMOGRAPHY STUDIES [J].
KISH, SJ ;
ZHONG, XH ;
HORNYKIEWICZ, O ;
HAYCOCK, JW .
ANNALS OF NEUROLOGY, 1995, 38 (02) :260-264
[34]  
Koller WC., 1997, MOVEMENT DISORDERS N, P125
[35]   HUMAN STRIATAL L-DOPA DECARBOXYLASE ACTIVITY ESTIMATED INVIVO USING 6-[F-18]FLUORO-DOPA AND POSITRON EMISSION TOMOGRAPHY - ERROR ANALYSIS AND APPLICATION TO NORMAL SUBJECTS [J].
KUWABARA, H ;
CUMMING, P ;
REITH, J ;
LEGER, G ;
DIKSIC, M ;
EVANS, AC ;
GJEDDE, A .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1993, 13 (01) :43-56
[36]   Comparison of methods for analysis of clinical [C-11]raclopride studies [J].
Lammertsma, AA ;
Bench, CJ ;
Hume, SP ;
Osman, S ;
Gunn, K ;
Brooks, DJ ;
Frackowiak, RSJ .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1996, 16 (01) :42-52
[37]  
Léger G, 1998, SYNAPSE, V30, P351, DOI 10.1002/(SICI)1098-2396(199812)30:4<351::AID-SYN2>3.0.CO
[38]  
2-2
[39]   EVIDENCE FOR LONG-TERM SURVIVAL AND FUNCTION OF DOPAMINERGIC GRAFTS IN PROGRESSIVE PARKINSONS-DISEASE [J].
LINDVALL, O ;
SAWLE, G ;
WIDNER, H ;
ROTHWELL, JC ;
BJORKLUND, A ;
BROOKS, D ;
BRUNDIN, P ;
FRACKOWIAK, R ;
MARSDEN, CD ;
ODIN, P ;
REHNCRONA, S .
ANNALS OF NEUROLOGY, 1994, 35 (02) :172-180
[40]   CLINICAL-APPLICATION OF NEURONAL GRAFTS IN PARKINSONS-DISEASE [J].
LINDVALL, O .
JOURNAL OF NEUROLOGY, 1994, 242 (01) :S54-S56