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

E. H. Danielsen, P. Cumming, F. Andersen, D. Bender, T. Brevig, L. Falborg, A. Gee, N. M. Gillings, S. B. Hansen, F. Hermansen, J. Johansen, T. E. Johansen, A. Dahl-Jørgensen, H. A. Jørgensen, M. Meyer, O. Munk, E. B. Pedersen, P. H. Poulsen, A. B. Rodell, M. Sakoh & 7 others C. Z. Simonsen, D. F. Smith, J. C. Sørensen, L. Østergård, J. Zimmer, A. Gjedde, A. Møller

Research output: Contribution to journalArticle

Abstract

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 and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete gila cell line-derived neurotrophic factor (GDNF) (≃2 ng GDNF/h/105 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 brains 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 that 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 [11C]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 [11C]raclopride to the dopamine D2-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.

Original languageEnglish (US)
Pages (from-to)247-259
Number of pages13
JournalCell Transplantation
Volume9
Issue number2
StatePublished - Mar 2000
Externally publishedYes

Fingerprint

MPTP Poisoning
Miniature Swine
Corpus Striatum
Positron emission tomography
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parkinson Disease
Swine
Tissue
Animals
Positron-Emission Tomography
Magnetic resonance
Surgery
Imaging techniques
Immunosuppression
Allografts
Nerve Growth Factors
Grafts
Rigidity
Neurons
Muscle

Keywords

  • Allografts
  • Animal models
  • Parkinson's disease
  • Positron emission tomography (PET)

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation

Cite this

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. / Danielsen, E. H.; Cumming, P.; Andersen, F.; Bender, D.; Brevig, T.; Falborg, L.; Gee, A.; Gillings, N. M.; Hansen, S. B.; Hermansen, F.; Johansen, J.; Johansen, T. E.; Dahl-Jørgensen, A.; Jørgensen, H. A.; Meyer, M.; Munk, O.; Pedersen, E. B.; Poulsen, P. H.; Rodell, A. B.; Sakoh, M.; Simonsen, C. Z.; Smith, D. F.; Sørensen, J. C.; Østergård, L.; Zimmer, J.; Gjedde, A.; Møller, A.

In: Cell Transplantation, Vol. 9, No. 2, 03.2000, p. 247-259.

Research output: Contribution to journalArticle

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-Jørgensen, A, Jørgensen, HA, Meyer, M, Munk, O, Pedersen, EB, Poulsen, PH, Rodell, AB, Sakoh, M, Simonsen, CZ, Smith, DF, Sørensen, JC, Østergård, L, Zimmer, J, Gjedde, A & Møller, A 2000, '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', Cell Transplantation, vol. 9, no. 2, pp. 247-259.
Danielsen, E. H. ; Cumming, P. ; Andersen, F. ; Bender, D. ; Brevig, T. ; Falborg, L. ; Gee, A. ; Gillings, N. M. ; Hansen, S. B. ; Hermansen, F. ; Johansen, J. ; Johansen, T. E. ; Dahl-Jørgensen, A. ; Jørgensen, H. A. ; Meyer, M. ; Munk, O. ; Pedersen, E. B. ; Poulsen, P. H. ; Rodell, A. B. ; Sakoh, M. ; Simonsen, C. Z. ; Smith, D. F. ; Sørensen, J. C. ; Østergård, L. ; Zimmer, J. ; Gjedde, A. ; Møller, A. / 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. In: Cell Transplantation. 2000 ; Vol. 9, No. 2. pp. 247-259.
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T1 - The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted to a minipig model of Parkinson's disease

T2 - Preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers

AU - Danielsen, E. H.

AU - Cumming, P.

AU - Andersen, F.

AU - Bender, D.

AU - Brevig, T.

AU - Falborg, L.

AU - Gee, A.

AU - Gillings, N. M.

AU - Hansen, S. B.

AU - Hermansen, F.

AU - Johansen, J.

AU - Johansen, T. E.

AU - Dahl-Jørgensen, A.

AU - Jørgensen, H. A.

AU - Meyer, M.

AU - Munk, O.

AU - Pedersen, E. B.

AU - Poulsen, P. H.

AU - Rodell, A. B.

AU - Sakoh, M.

AU - Simonsen, C. Z.

AU - Smith, D. F.

AU - Sørensen, J. C.

AU - Østergård, L.

AU - Zimmer, J.

AU - Gjedde, A.

AU - Møller, A.

PY - 2000/3

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N2 - 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 and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete gila cell line-derived neurotrophic factor (GDNF) (≃2 ng GDNF/h/105 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 brains 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 that 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 [11C]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 [11C]raclopride to the dopamine D2-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.

AB - 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 and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete gila cell line-derived neurotrophic factor (GDNF) (≃2 ng GDNF/h/105 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 brains 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 that 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 [11C]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 [11C]raclopride to the dopamine D2-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.

KW - Allografts

KW - Animal models

KW - Parkinson's disease

KW - Positron emission tomography (PET)

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