Skip to main content
SpringerLink
Log in

Behavior, PET and histology in novel regimen of MPTP marmoset model of Parkinson’s disease for long-term stem cell therapy

  • Original Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Stem cell technologies are particularly attractive in Parkinson’s disease (PD) research although they occasionally need long-term treatment for anti-parkinsonian activity. Unfortunately, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) widely used as a model for PD has several limitations, including the risk of dose-dependent mortality and the difficulty of maintenance of PD symptoms during the whole experiment period. Therefore, we tested if our novel MPTP regimen protocol (2 mg/kg for 2 consecutive days and 1 mg/kg for next 3 consecutive days) can be maintained stable parkinsonism without mortality for long-term stem cell therapy. For this, we used small-bodied common marmoset monkeys (Callithrix jacchus) among several nonhuman primates showing high anatomical, functional, and behavioral similarities to humans. Along with no mortality, the behavioral changes involved in PD symptoms were maintained for 32 weeks. Also, the loss of jumping ability of the MPTP-treated marmosets in the Tower test was not recovered by 32 weeks. Positron emission tomography (PET) analysis revealed that remarkable decreases of bindings of 18F-FP-CIT were observed at the striatum of the brains of the marmosets received MPTP during the full period of the experiment for 32 weeks. In the substantia nigra of the marmosets, the loss of tyrosine hydroxylase (TH) immunoreactivity was also observed at 32 weeks following the MPTP treatment. In conclusion, our low-dose MPTP regimen protocol was found to be stable parkinsonism without mortality as evidenced by behavior, PET, and TH immunohistochemistry. This result will be useful for evaluation of possible long-term stem cell therapy for anti-parkinsonian activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Khan W, Priyadarshini M, Zakai HA, Kamal MA, Alam Q. A brief overview of tyrosine hydroxylase and a-synuclein in the Parkinsonian brain. CNS Neurol Disord Drug Targets 2012;11:456–462.

    Article  CAS  PubMed  Google Scholar 

  2. Barker RA, Drouin-Ouellet J, Parmar M. Cell-based therapies for Parkinson disease-past insights and future potential. Nat Rev Neurol 2015;11:492–503.

    Article  CAS  PubMed  Google Scholar 

  3. Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep 2012;1:703–714.

    Article  CAS  PubMed  Google Scholar 

  4. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 2011;480:547–551.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, et al. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell 2015;16:269–274.

    Article  CAS  PubMed  Google Scholar 

  6. Offen D, Barhum Y, Levy YS, Burshtein A, Panet H, Cherlow T, et al. Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson’s disease. J Neural Transm Suppl 2007;(72):133–143.

    Article  CAS  PubMed  Google Scholar 

  7. Sánchez-Pernaute R, Studer L, Bankiewicz KS, Major EO, McKay RD. In vitro generation and transplantation of precursor-derived human dopamine neurons. J Neurosci Res 2001;65:284–288.

    Article  PubMed  Google Scholar 

  8. Le W, Sayana P, Jankovic J. Animal models of Parkinson’s disease: a gateway to therapeutics? Neurotherapeutics 2014;11:92–110.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Blandini F, Armentero MT. Animal models of Parkinson’s disease. FEBS J 2012;279:1156–1166.

    Article  CAS  PubMed  Google Scholar 

  10. Kelava I, Reillo I, Murayama AY, Kalinka AT, Stenzel D, Tomancak P, et al. Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus. Cereb Cortex 2012;22:469–481.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Smith D, Trennery P, Farningham D, Klapwijk J. The selection of marmoset monkeys (Callithrix jacchus) in pharmaceutical toxicology. Lab Anim 2001;35:117–130.

    Article  CAS  PubMed  Google Scholar 

  12. Dell’Mour V, Range F, Huber L. Social learning and mother’s behavior in manipulative tasks in infant marmosets. Am J Primatol 2009;71:503–509.

    Article  PubMed  Google Scholar 

  13. Eslamboli A. Marmoset monkey models of Parkinson’s disease: which model, when and why? Brain Res Bull 2005;68:140–149.

    Article  PubMed  Google Scholar 

  14. Owen S, Thomas C, West P, Wolfensohn S, Wood M. Report on primate supply for biomedical scientific work in the UK. EUPREN UK Working Party. Lab Anim 1997;31:289–297.

    Article  CAS  PubMed  Google Scholar 

  15. Sasaki E. Prospects for genetically modified non-human primate models, including the common marmoset. Neurosci Res 2015;93:110–115.

    Article  CAS  PubMed  Google Scholar 

  16. Sasaki E, Suemizu H, Shimada A, Hanazawa K, Oiwa R, Kamioka M, et al. Generation of transgenic non-human primates with germline transmission. Nature 2009;459:523–527.

    Article  CAS  PubMed  Google Scholar 

  17. Bezard E, Przedborski S. A tale on animal models of Parkinson’s disease. Mov Disord 2011;26:993–1002.

    Article  PubMed  Google Scholar 

  18. Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson’s disease. Neuron 2010;66:646–661.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Tieu K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb Perspect Med 2011;1:a009316.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979;1:249–254.

    Article  CAS  PubMed  Google Scholar 

  21. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 1983;80:4546–4550.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Bezard E, Imbert C, Deloire X, Bioulac B, Gross CE. A chronic MPTP model reproducing the slow evolution of Parkinson’s disease: evolution of motor symptoms in the monkey. Brain Res 1997;766:107–112.

    Article  CAS  PubMed  Google Scholar 

  23. Duty S, Jenner P. Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 2011;164:1357–1391.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Pearce RK, Jackson M, Britton DR, Shiosaki K, Jenner P, Marsden CD. Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets. Psychopharmacology (Berl) 1999;142:51–60.

    Article  CAS  Google Scholar 

  25. Verhave PS, Vanwersch RA, van Helden HP, Smit AB, Philippens IH. Two new test methods to quantify motor deficits in a marmoset model for Parkinson’s disease. Behav Brain Res 2009;200:214–219.

    Article  PubMed  Google Scholar 

  26. Lundkvist C, Halldin C, Ginovart N, Swahn CG, Farde L. [18F] beta-CITFP is superior to [11C] beta-CIT-FP for quantitation of the dopamine transporter. Nucl Med Biol 1997;24:621–627.

    Article  CAS  PubMed  Google Scholar 

  27. Jenner P, Rupniak NM, Rose S, Kelly E, Kilpatrick G, Lees A, et al. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset. Neurosci Lett 1984;50:85–90.

    Article  CAS  PubMed  Google Scholar 

  28. Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, et al. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 2001;76:1265–74.

    Article  CAS  PubMed  Google Scholar 

  29. Buchanan-Smith HM, Shand C, Morris K. Cage use and feeding height preferences of captive common marmosets (Callithrix j. jacchus) in twotier cages. J Appl Anim Welf Sci 2002;5:139–149.

    Article  CAS  Google Scholar 

  30. Pearce RK, Jackson M, Smith L, Jenner P, Marsden CD. Chronic L-DOPA administration induces dyskinesias in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmoset (Callithrix Jacchus). Mov Disord 1995;10:731–740.

    Article  CAS  PubMed  Google Scholar 

  31. Silverdale MA, Nicholson SL, Crossman AR, Brotchie JM. Topiramate reduces levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson’s disease. Mov Disord 2005;20:403–409.

    Article  PubMed  Google Scholar 

  32. Hantraye P, Loc’h C, Tacke U, Riche D, Stulzaft O, Doudet D, et al. “In vivo” visualization by positron emission tomography of the progressive striatal dopamine receptor damage occurring in MPTP-intoxicated nonhuman primates. Life Sci 1986;39:1375–1382.

    Article  CAS  PubMed  Google Scholar 

  33. Luquin MR, Manrique M, Guillén J, Arbizu J, Ordoñez C, Marcilla I. Enhanced GDNF expression in dopaminergic cells of monkeys grafted with carotid body cell aggregates. Brain Res 2011;1375:120–127.

    Article  CAS  PubMed  Google Scholar 

  34. Schwarz J. [Nuclear medicine imaging in patients with Parkinson’s syndrome: an update]. Nervenarzt 2010;81:1160–1167.

    Article  CAS  PubMed  Google Scholar 

  35. Nagai Y, Obayashi S, Ando K, Inaji M, Maeda J, Okauchi T, et al. Progressive changes of pre-and post-synaptic dopaminergic biomarkers in conscious MPTP-treated cynomolgus monkeys measured by positron emission tomography. Synapse 2007;61:809–819.

    Article  CAS  PubMed  Google Scholar 

  36. Saiki H, Hayashi T, Takahashi R, Takahashi J. Objective and quantitative evaluation of motor function in a monkey model of Parkinson’s disease. J Neurosci Methods 2010;190:198–204.

    Article  CAS  PubMed  Google Scholar 

  37. Masilamoni G, Votaw J, Howell L, Villalba RM, Goodman M, Voll RJ, et al. (18)F-FECNT: validation as PET dopamine transporter ligand in parkinsonism. Exp Neurol 2010;226:265–273.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Iravani MM, Haddon CO, Cooper JM, Jenner P, Schapira AH. Pramipexole protects against MPTP toxicity in non-human primates. J Neurochem 2006;96:1315–1321.

    Article  CAS  PubMed  Google Scholar 

  39. Iravani MM, Syed E, Jackson MJ, Johnston LC, Smith LA, Jenner P. A modified MPTP treatment regime produces reproducible partial nigrostriatal lesions in common marmosets. Eur J Neurosci 2005;21:841–854.

    Article  PubMed  Google Scholar 

  40. Jackson MJ, Jenner P. The MPTP-treated primate with specific reference to the use of the common marmoset (Callithrix jacchus). Neuromethods 2012;61:371–400.

    Article  Google Scholar 

  41. Philippens IH, Wubben JA, Finsen B, Hart BA. Oral treatment with the NADPH oxidase antagonist apocynin mitigates clinical and pathological features of parkinsonism in the MPTP marmoset model. J Neuroimmune Pharmacol 2013;8:715–726.

    Article  PubMed  Google Scholar 

  42. Huot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, et al. UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances L-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset. Neuropharmacology 2014;82:76–87.

    Article  CAS  PubMed  Google Scholar 

  43. Hurley MJ, Jackson MJ, Smith LA, Rose S, Jenner P. Proteomic analysis of striatum from MPTP-treated marmosets (Callithrix jacchus) with LDOPA-induced dyskinesia of differing severity. J Mol Neurosci 2014;52:302–312.

    Article  CAS  PubMed  Google Scholar 

  44. Hansard MJ, Jackson MJ, Smith LA, Rose S, Jenner P. A major metabolite of bupropion reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Behav Pharmacol 2011;22:269–274.

    Article  CAS  PubMed  Google Scholar 

  45. Johnston TH, Huot P, Fox SH, Wakefield JD, Sykes KA, Bartolini WP, et al. Fatty acid amide hydrolase (FAAH) inhibition reduces L-3,4-dihydroxyphenylalanine-induced hyperactivity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primate model of Parkinson’s disease. J Pharmacol Exp Ther 2011;336:423–430.

    Article  CAS  PubMed  Google Scholar 

  46. Jones CA, Johnston LC, Jackson MJ, Smith LA, van Scharrenburg G, Rose S, et al. An in vivo pharmacological evaluation of pardoprunox (SLV308)—a novel combined dopamine D(2)/D(3) receptor partial agonist and 5-HT(1A) receptor agonist with efficacy in experimental models of Parkinson’s disease. Eur Neuropsychopharmacol 2010;20:582–593.

    Article  CAS  PubMed  Google Scholar 

  47. Yabe H, Choudhury ME, Kubo M, Nishikawa N, Nagai M, Nomoto M. Zonisamide increases dopamine turnover in the striatum of mice and common marmosets treated with MPTP. J Pharmacol Sci 2009;110:64–68.

    Article  CAS  PubMed  Google Scholar 

  48. Nash JE, Ravenscroft P, McGuire S, Crossman AR, Menniti FS, Brotchie JM. The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson’s disease. Exp Neurol 2004;188:471–479.

    Article  CAS  PubMed  Google Scholar 

  49. Nomoto M, Kita S, Iwata SI, Kaseda S, Fukuda T. Effects of acute or prolonged administration of cabergoline on parkinsonism induced by MPTP in common marmosets. Pharmacol Biochem Behav 1998;59:717–721.

    Article  CAS  PubMed  Google Scholar 

  50. Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2007;2:141–151.

    Article  CAS  PubMed  Google Scholar 

  51. Potts LF, Wu H, Singh A, Marcilla I, Luquin MR, Papa SM. Modeling Parkinson’s disease in monkeys for translational studies, a critical analysis. Exp Neurol 2014;256:133–143.

    Article  CAS  PubMed  Google Scholar 

  52. Ando K, Obayashi S, Nagai Y, Oh-Nishi A, Minamimoto T, Higuchi M, et al. PET analysis of dopaminergic neurodegeneration in relation to immobility in the MPTP-treated common marmoset, a model for Parkinson’s disease. PLoS One 2012;7:e46371.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 2010;67:715–725.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Takagi Y, Takahashi J, Saiki H, Morizane A, Hayashi T, Kishi Y, et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 2005;115:102–109.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Kikuchi T, Morizane A, Doi D, Onoe H, Hayashi T, Kawasaki T, et al. Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson’s disease. J Parkinsons Dis 2011;1:395–412.

    CAS  PubMed  Google Scholar 

  56. Yi BR, Kim SU, Choi KC. Development and application of neural stem cells for treating various human neurological diseases in animal models. Lab Anim Res 2013;29:131–137.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 2000;290:767–773.

    Article  CAS  PubMed  Google Scholar 

  58. Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS. Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 2001;106:589–601.

    Article  CAS  PubMed  Google Scholar 

  59. Eidelberg E, Brooks BA, Morgan WW, Walden JG, Kokemoor RH. Variability and functional recovery in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism in monkeys. Neuroscience 1986;18:817–822.

    Article  CAS  PubMed  Google Scholar 

  60. Close SP, Elliott PJ, Hayes AG, Marriott AS. Effects of classical and novel agents in a MPTP-induced reversible model of Parkinson’s disease. Psychopharmacology (Berl) 1990;102:295–300.

    Article  CAS  Google Scholar 

  61. Maneuf YP, Mitchell IJ, Crossman AR, Woodruff GN, Brotchie JM. Functional implications of kappa opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson’s disease. Brain Res 1995;683:102–108.

    Article  CAS  PubMed  Google Scholar 

  62. Ando K, Maeda J, Inaji M, Okauchi T, Obayashi S, Higuchi M, et al. Neurobehavioral protection by single dose l-deprenyl against MPTP-induced parkinsonism in common marmosets. Psychopharmacology (Berl) 2008;195:509–516.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea

    Jun-Won Yun, Jae-Bum Ahn, Euna Kwon, Jae Hun Ahn & Byeong-Cheol Kang

  2. Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea

    Jae-Bum Ahn, Jae Hun Ahn & Byeong-Cheol Kang

  3. Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea

    Hyung Woo Park & Sun Ha Paek

  4. Department of Biomedical Sciences, Seoul National University, Seoul, Korea

    Hwon Heo & Hyeonjin Kim

  5. Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia

    Jin-Sung Park

  6. Department of Radiology, Seoul National University Hospital, Seoul, Korea

    Hyeonjin Kim

  7. Designed Animal and Transplantation Research Institute, Institute of GreenBio Science Technology, Seoul National University, Pyeongchang, Korea

    Byeong-Cheol Kang

Authors
  1. Jun-Won Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae-Bum Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Euna Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae Hun Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyung Woo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hwon Heo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin-Sung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hyeonjin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sun Ha Paek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Byeong-Cheol Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Byeong-Cheol Kang.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yun, JW., Ahn, JB., Kwon, E. et al. Behavior, PET and histology in novel regimen of MPTP marmoset model of Parkinson’s disease for long-term stem cell therapy. Tissue Eng Regen Med 13, 100–109 (2016). https://doi.org/10.1007/s13770-015-0106-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-015-0106-3

Keywords

Search

Navigation