Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2015 Sep 15;31(6):705–713. doi: 10.1007/s12264-015-1559-z

Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates

Arun Singh 1, Claire A Gutekunst 2, Subramaniam Uthayathas 1, John P M Finberg 3, Klaus Mewes 4, Robert E Gross 2, Stella M Papa 1,4, Yair Feld 5,✉
PMCID: PMC5278775  NIHMSID: NIHMS845214  PMID: 26373985

Abstract

Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson’s disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6–8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.

Keywords: globus pallidum, autologous, levodopa, antiparkinsonian, monkeys

References

  • [1].Bergman H, Wichmann T, Karmon B D, Long MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol. 1994;72:507–520. doi: 10.1152/jn.1994.72.2.507. [DOI] [PubMed] [Google Scholar]
  • [2].Plenz D, Kital ST. A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature. 1999;400:677–682. doi: 10.1038/23281. [DOI] [PubMed] [Google Scholar]
  • [3].Rivlin-Etzion M, Marmor O, Heimer G, Raz A, Nini A, Bergman H. Basal ganglia oscillations and pathophysiology of movement disorders. Curr Opin Neurobiol. 2006;16:629–637. doi: 10.1016/j.conb.2006.10.002. [DOI] [PubMed] [Google Scholar]
  • [4].Soares J, Kliem MA, Betarbet R, Greenamyre JT, Yamamoto B, Wichmann T. Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J Neurosci. 2004;24:6417–6426. doi: 10.1523/JNEUROSCI.0836-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Finberg JP, Gluzman Z, Reshef M, Loboda Y, Mohsen U, Bressler-Stramer T, et al. Modulation of excessive neuronal activity by fibroblasts: potential use in treatment of Parkinson’s disease. Restor Neurol Neurosci. 2010;28:803–815. doi: 10.3233/RNN-2010-0551. [DOI] [PubMed] [Google Scholar]
  • [6].Fahn S. Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci. 2003;991:1–14. doi: 10.1111/j.1749-6632.2003.tb07458.x. [DOI] [PubMed] [Google Scholar]
  • [7].Obeso JA, Rodriguez-Oroz MC, Rodriguez M, Lanciego JL, Artieda J, Gonzalo N, et al. Trends Neurosci. 2000. Pathophysiology of the basal ganglia in Parkinson’s disease; p. 23. [DOI] [PubMed] [Google Scholar]
  • [8].Kopell BH, Rezai AR, Chang JW, Vitek JL. Mov Disord. 2006. Anatomy and physiology of the basal ganglia: implications for deep brain stimulation for Parkinson’s disease; p. 21. [DOI] [PubMed] [Google Scholar]
  • [9].Lozano A, Lang A, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchison W, et al. Effect of GPi pallidotomy on motor function in Parkinson’s disease. The Lancet. 1995;346:1383–1387. doi: 10.1016/S0140-6736(95)92404-3. [DOI] [PubMed] [Google Scholar]
  • [10].Cenci MA. Dopamine dysregulation of movement control in L-DOPA-induced dyskinesia. Trends Neurosci. 2007;30:236–243. doi: 10.1016/j.tins.2007.03.005. [DOI] [PubMed] [Google Scholar]
  • [11].Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2:577–588. doi: 10.1038/35086062. [DOI] [PubMed] [Google Scholar]
  • [12].Heimer G, Bar-Gad I, Goldberg JA, Bergman H. Dopamine replacement therapy reverses abnormal synchronization of pallidal neurons in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine primate model of parkinsonism. J Neurosci. 2002;22:7850–7855. doi: 10.1523/JNEUROSCI.22-18-07850.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Benazzouz A, et al. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain. 1998;121:451–457. doi: 10.1093/brain/121.3.451. [DOI] [PubMed] [Google Scholar]
  • [14].Levy R, Hutchison WD, Lozano AM, Dostrovsky JO. Synchronized neuronal discharge in the basal ganglia of parkinsonian patients is limited to oscillatory activity. J Neurosci. 2002;22:2855–2861. doi: 10.1523/JNEUROSCI.22-07-02855.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Wu Y, Levy R, Ashby P, Tasker R, Dostrovsky J. Does stimulation of the GPi control dyskinesia by activating inhibitory axons? Mov Disord. 2001;16:208–216. doi: 10.1002/mds.1046. [DOI] [PubMed] [Google Scholar]
  • [16].Papa SM, Chase TN. Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Ann Neurol. 1996;39:574–578. doi: 10.1002/ana.410390505. [DOI] [PubMed] [Google Scholar]
  • [17].Bedard PJ, Di Paolo T, Falardeau P, Boucher R. Chronic treatment with L-DOPA, but not bromocriptine induces dyskinesia in MPTP-parkinsonian monkeys. Correlation with [3H]spiperone binding. Brain Res. 1986;379:294–299. doi: 10.1016/0006-8993(86)90783-3. [DOI] [PubMed] [Google Scholar]
  • [18].Winters WD, Kado RT. A stereotaxic brain atlas for Nacaca Nemestrina. 1969. [Google Scholar]
  • [19].Liang L, DeLong MR, Papa SM. Inversion of dopamine responses in striatal medium spiny neurons and involuntary movements. J Neurosci. 2008;28:7537–7547. doi: 10.1523/JNEUROSCI.1176-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].DeLong MR, Crutcher MD, Georgopoulos AP. Primate globus pallidus and subthalamic nucleus: functional organization. J Neurophysiol. 1985;53:530–543. doi: 10.1152/jn.1985.53.2.530. [DOI] [PubMed] [Google Scholar]
  • [21].Gutekunst CA, Stewart EN, Gross RE. Front Neuroanat. 2010. Immunohistochemical Distribution of PlexinA4 in the Adult Rat Central Nervous System; p. 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Gutekunst CA, Levey AI, Heilman CJ, Whaley WL, Yi H, Nash NR, et al. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci U S A. 1995;92:8710–8714. doi: 10.1073/pnas.92.19.8710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Smith DE, Roberts J, Gage FH, Tuszynski MH. Ageassociated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc Natl Acad Sci U S A. 1999;96:10893–10898. doi: 10.1073/pnas.96.19.10893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Fast VG, Darrow BJ, Saffitz JE, Kleber AG. Anisotropic activation spread in heart cell monolayers assessed by highresolution optical mapping. Role of tissue discontinuities. Circ Res. 1996;79:115–127. doi: 10.1161/01.res.79.1.115. [DOI] [PubMed] [Google Scholar]
  • [25].Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J, et al. Convection-enhanced delivery of AAV vector in Parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol. 2000;164:2–14. doi: 10.1006/exnr.2000.7408. [DOI] [PubMed] [Google Scholar]
  • [26].Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff D O, Malley KL, et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet. 1994;8:148–154. doi: 10.1038/ng1094-148. [DOI] [PubMed] [Google Scholar]
  • [27].Wernig M, Zhao J-P, Pruszak J, Hedlund E, Fu D, Soldner F, et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A. 2008;105:5856–5861. doi: 10.1073/pnas.0801677105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Levivier M, Przedborski S, Bencsics C, Kang UJ. Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci. 1995;15:7810–7820. doi: 10.1523/JNEUROSCI.15-12-07810.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Jankovic J, Lai E, Ben-Arie L, Krauss JK, Grossman R. Levodopa-induced dyskinesias treated by pallidotomy. J Neurol Sci. 1999;167:62–67. doi: 10.1016/S0022-510X(99)00141-0. [DOI] [PubMed] [Google Scholar]
  • [30].Kleiner-Fisman G L n A, Moro E, Poon YY, Lang AE. Long-term effect of unilateral pallidotomy on levodopainduced dyskinesia. Mov Disord. 2010;25:1496–1498. doi: 10.1002/mds.23155. [DOI] [PubMed] [Google Scholar]
  • [31].Singh A, Kammermeier S, Mehrkens JH, Botzel K. Movement kinematic after deep brain stimulation associated microlesions. J Neurol Neurosurg Psychiatry. 2012;83:1022–1026. doi: 10.1136/jnnp-2012-302309. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES