Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-dopa uptake and metabolism after intracerebral implantation in nonhuman primates

Thyagarajan Subramanian, Dwaine F. Emerich, Roy A.E. Bakay, John M. Hoffman, Mark M. Goodman, Timothy M. Shoup, Gary W. Miller, Allan I. Levey, George W. Hubert, Scott Batchelor, Shelly R. Winn, Joel A. Saydoff, Ray L. Watts

Research output: Contribution to journalArticle

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Abstract

Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 108 fmol/min x 106 cells, and that this uptake can be specifically blocked 88% by the addition of 10 nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP- treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5- 13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer- encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)469-477
Number of pages9
JournalCell Transplantation
Volume6
Issue number5
DOIs
StatePublished - Sep 1 1997

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Dihydroxyphenylalanine
Metabolism
Primates
Dopamine
Polymers
Positron emission tomography
Positron-Emission Tomography
Haplorhini
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Brain
Capsules
Parkinson Disease
Nomifensine
Magnetic resonance
In Vitro Techniques
Corpus Striatum
Surgery
Animals
Experiments
Cells

All Science Journal Classification (ASJC) codes

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

Cite this

Subramanian, Thyagarajan ; Emerich, Dwaine F. ; Bakay, Roy A.E. ; Hoffman, John M. ; Goodman, Mark M. ; Shoup, Timothy M. ; Miller, Gary W. ; Levey, Allan I. ; Hubert, George W. ; Batchelor, Scott ; Winn, Shelly R. ; Saydoff, Joel A. ; Watts, Ray L. / Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-dopa uptake and metabolism after intracerebral implantation in nonhuman primates. In: Cell Transplantation. 1997 ; Vol. 6, No. 5. pp. 469-477.
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abstract = "Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 108 fmol/min x 106 cells, and that this uptake can be specifically blocked 88{\%} by the addition of 10 nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP- treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5- 13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer- encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.",
author = "Thyagarajan Subramanian and Emerich, {Dwaine F.} and Bakay, {Roy A.E.} and Hoffman, {John M.} and Goodman, {Mark M.} and Shoup, {Timothy M.} and Miller, {Gary W.} and Levey, {Allan I.} and Hubert, {George W.} and Scott Batchelor and Winn, {Shelly R.} and Saydoff, {Joel A.} and Watts, {Ray L.}",
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Subramanian, T, Emerich, DF, Bakay, RAE, Hoffman, JM, Goodman, MM, Shoup, TM, Miller, GW, Levey, AI, Hubert, GW, Batchelor, S, Winn, SR, Saydoff, JA & Watts, RL 1997, 'Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-dopa uptake and metabolism after intracerebral implantation in nonhuman primates', Cell Transplantation, vol. 6, no. 5, pp. 469-477. https://doi.org/10.1016/S0963-6897(97)00049-3

Polymer-encapsulated PC-12 cells demonstrate high-affinity uptake of dopamine in vitro and 18F-dopa uptake and metabolism after intracerebral implantation in nonhuman primates. / Subramanian, Thyagarajan; Emerich, Dwaine F.; Bakay, Roy A.E.; Hoffman, John M.; Goodman, Mark M.; Shoup, Timothy M.; Miller, Gary W.; Levey, Allan I.; Hubert, George W.; Batchelor, Scott; Winn, Shelly R.; Saydoff, Joel A.; Watts, Ray L.

In: Cell Transplantation, Vol. 6, No. 5, 01.09.1997, p. 469-477.

Research output: Contribution to journalArticle

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AU - Subramanian, Thyagarajan

AU - Emerich, Dwaine F.

AU - Bakay, Roy A.E.

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AU - Goodman, Mark M.

AU - Shoup, Timothy M.

AU - Miller, Gary W.

AU - Levey, Allan I.

AU - Hubert, George W.

AU - Batchelor, Scott

AU - Winn, Shelly R.

AU - Saydoff, Joel A.

AU - Watts, Ray L.

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N2 - Intracranial implantation of polymer-encapsulated PC-12 cells has been shown to improve motor behavioral performance in animal models of Parkinson's disease. The purpose of this blinded study was to examine whether such improvement is associated with the active uptake and metabolism of dopamine precursors by intracerebrally implanted polymer-encapsulated PC-12 cells. In an in vitro experiment we demonstrate that 3H-dopamine uptake by PC-12 cells was 108 fmol/min x 106 cells, and that this uptake can be specifically blocked 88% by the addition of 10 nM of nomifensine. In the in vivo experiments, polymer-encapsulated PC-12 cells were implanted in four MPTP- treated monkeys into the left deep parietal white matter (R1) or left striatum (R2-4). A fifth MPTP-treated monkey (R5) served as a control and received left striatal implants of empty capsules. 18F-Dopa Positron Emission Tomography (PET) imaging was performed on each monkey before and after implantation surgery by blinded investigators. PET images obtained 5- 13 wk after implantation demonstrated well delineated focal areas of high 18F-dopa uptake in R1, R2, and R4. The focal area of high 18F-dopa uptake in R1 precisely coregistered on a brain magnetic resonance image to the site of implantation. R3 (in whom the polymer-encapsulated PC-12 cells demonstrated poor cell survival upon explantation) and R5 (empty capsules) failed to demonstrate any area of increased 18F-dopa uptake in their PET images. Histological examination of the host brain revealed no sprouting of dopaminergic nerve terminals around the implantation sites of the polymer- encapsulated PC-12 cells. These results indicate that the previously noted behavioral improvement after intrastriatal implantation of polymer encapsulated PC-12 cells is at least in part due to their highly specific uptake and metabolism of dopamine precursors. Furthermore, these data suggest that polymer-encapsulated PC-12 cells can store, reuptake, and functionally replenish dopamine and therefore, may be an effective treatment for Parkinson's disease.

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