Advertisement

Clinical Autonomic Research

, Volume 29, Issue 4, pp 415–425 | Cite as

Cardiac sympathetic innervation in the MPTP non-human primate model of Parkinson disease

  • Mar Carmona-AbellanEmail author
  • Ivan Martínez-Valbuena
  • Carla DiCaudo
  • Irene Marcilla
  • Maria Rosario Luquin
Research Article

Abstract

Purpose

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces degeneration of dopaminergic neurons and reproduces the motor features of Parkinson disease (PD); however, the effect of MPTP on extranigral structures has been poorly studied. The aim of this research was to study the cardiac sympathetic innervation of control and MPTP-treated monkeys in order to describe the influence of MPTP toxicity on cardiac tissue.

Methods

Eight monkeys were included in the study and divided into two groups, four monkeys serving as controls and four forming the MPTP group. Sections from the anterior left ventricle were immunohistochemically examined to characterize the sympathetic fibers of cardiac tissue. The intensity of immunoreactivity in the nerve fibers was quantitatively analyzed using ImageJ software.

Results

As occurs in PD, the sympathetic peripheral nervous system is affected in MPTP-treated monkeys. The percentage of tyrosine hydroxylase immunoreactive fibers in the entire fascicle area was markedly lower in the MPTP group (24.23%) than the control group (35.27%) (p < 0.05), with preservation of neurofilament immunoreactive fibers in the epicardium of MPTP-treated monkeys. Alpha-synuclein deposits were observed in sections of the anterior left ventricle of MPTP-treated monkeys but not in control animals, whereas phosphorylated synuclein aggregates were not observed in either controls or MPTP-treated monkeys.

Conclusion

The peripheral autonomic system can also be affected by neurotoxins that specifically inhibit mitochondrial complex I.

Keywords

Cardiac innervation MPTP Animal models Parkinson disease Non-motor symptoms 

Notes

Funding

This study was partially co-funded by the Instituto de Salud Carlos III through project PI12/01730 from the Spanish Health Research Fund (FIS) and the Association of Friends (ADA) of the University of Navarra (MCA).

Compliance with ethical standards

Conflict of interest

None of the authors have any conflicts of interest to report.

Supplementary material

10286_2019_620_MOESM1_ESM.pzfx (7 kb)
Supplementary material 1 (PZFX 7 kb)

References

  1. 1.
    Stephenson R, Siderowf A, Stern MB (2009) Premotor Parkinson’s disease: clinical features and detection strategies. Mov Disord 24 Suppl 2(2):S665–S670CrossRefGoogle Scholar
  2. 2.
    Wolters E (2009) Non-motor extranigral signs and symptoms in Parkinson’s disease. Parkinsonism Relat Disord 15 Suppl 3(3):S6–S12CrossRefGoogle Scholar
  3. 3.
    Dickson DW, Fujishiro H, Orr C, DelleDonne A, Josephs KA, Frigerio R et al (2009) Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 15 Suppl 3(3):S1–S5CrossRefGoogle Scholar
  4. 4.
    Kaufmann H, Goldstein DS (2013) Autonomic dysfunction in Parkinson disease. Handb Clin Neurol 117:259–278CrossRefGoogle Scholar
  5. 5.
    Kaufmann H, Nahm K, Purohit D, Wolfe D (2004) Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63(6):1093–1095CrossRefGoogle Scholar
  6. 6.
    Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M et al (2007) Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders? A cohort study. Neurology 68(23):2012–2018CrossRefGoogle Scholar
  7. 7.
    Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113(4):421–429CrossRefGoogle Scholar
  8. 8.
    Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W et al (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30(12):1591–1601CrossRefGoogle Scholar
  9. 9.
    Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133(5):338–347CrossRefGoogle Scholar
  10. 10.
    Tijero B, Gomez-Esteban JC, Lezcano E, Fernandez-Gonzalez C, Somme J, Llorens V et al (2013) Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the alpha synuclein gene. Parkinsonism Relat Disord 19(1):95–100CrossRefGoogle Scholar
  11. 11.
    Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15(1):29–34CrossRefGoogle Scholar
  12. 12.
    Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22(8):3090–3099CrossRefGoogle Scholar
  13. 13.
    Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25(1):239–252CrossRefGoogle Scholar
  14. 14.
    Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61(5):413–426CrossRefGoogle Scholar
  15. 15.
    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL et al (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119(6):689–702CrossRefGoogle Scholar
  16. 16.
    Donadio V, Incensi A, Leta V, Giannoccaro MP, Scaglione C, Martinelli P et al (2014) Skin nerve alpha-synuclein deposits: a biomarker for idiopathic Parkinson disease. Neurology 82(15):1362–1369CrossRefGoogle Scholar
  17. 17.
    Wang N, Gibbons CH, Lafo J, Freeman R (2013) α-Synuclein in cutaneous autonomic nerves. Neurology 81(18):1604–1610CrossRefGoogle Scholar
  18. 18.
    Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K et al (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131(Pt 3):642–650CrossRefGoogle Scholar
  19. 19.
    Orimo S, Suzuki M, Inaba A, Mizusawa H (2012) 123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord 18(5):494–500CrossRefGoogle Scholar
  20. 20.
    Ren J, Porter JE, Wold LE, Aberle NS, Muralikrishnan D, Haselton JR (2004) Depressed contractile function and adrenergic responsiveness of cardiac myocytes in an experimental model of Parkinson disease, the MPTP-treated mouse. Neurobiol Aging 25(1):131–138CrossRefGoogle Scholar
  21. 21.
    Amino T, Uchihara T, Tsunekawa H, Takahata K, Shimazu S, Mizusawa H et al (2008) Myocardial nerve fibers are preserved in MPTP-treated mice, despite cardiac sympathetic dysfunction. Neurosci Res 60(3):314–318CrossRefGoogle Scholar
  22. 22.
    Metzger JM, Emborg ME (2019) Autonomic dysfunction in Parkinson disease and animal models. Clin Auton Res.  https://doi.org/10.1007/s10286-018-00584-7
  23. 23.
    Pérez-Otaño I, Oset C, Luquin MR, Herrero MT, Obeso JA, Del Río J (1994) MPTP-induced parkinsonism in primates: pattern of striatal dopamine loss following acute and chronic administration. Neurosci Lett 175(1–2):121–125CrossRefGoogle Scholar
  24. 24.
    Orimo S, Oka T, Miura H, Tsuchiya K, Mori F, Wakabayashi K et al (2002) Sympathetic cardiac denervation in Parkinson’s disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 73(6):776–777CrossRefGoogle Scholar
  25. 25.
    Orimo S, Amino T, Itoh Y, Takahashi A, Kojo T, Uchihara T et al (2005) Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 109(6):583–588CrossRefGoogle Scholar
  26. 26.
    Beach TG, White CL, Hamilton RL, Duda JE, Iwatsubo T, Dickson DW et al (2008) Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 116(3):277–288CrossRefGoogle Scholar
  27. 27.
    Blesa J, Przedborski S (2014) Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 8(155):155Google Scholar
  28. 28.
    Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74(2):721–729CrossRefGoogle Scholar
  29. 29.
    Kowall NW, Hantraye P, Brouillet E, Beal MF, McKee AC, Ferrante RJ (2000) MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons. Neuroreport 11(1):211–213CrossRefGoogle Scholar
  30. 30.
    Forno LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA (1986) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 20(4):449–455CrossRefGoogle Scholar
  31. 31.
    Goldstein DS, Holmes C, Kopin IJ, Sharabi Y (2011) Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. J Clin Invest 121(8):3320–3330CrossRefGoogle Scholar
  32. 32.
    Sharabi Y, Imrich R, Holmes C, Pechnik S, Goldstein DS (2008) Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson’s disease with orthostatic hypotension. Mov Disord 23(12):1725–1732CrossRefGoogle Scholar
  33. 33.
    Sharabi Y, Li ST, Dendi R, Holmes C, Goldstein DS (2003) Neurotransmitter specificity of sympathetic denervation in Parkinson’s disease. Neurology 60(6):1036–1039CrossRefGoogle Scholar
  34. 34.
    Gjerloff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S et al (2015) Imaging acetylcholinesterase density in peripheral organs in Parkinson’s disease with 11C-donepezil PET. Brain 138(Pt 3):653–663CrossRefGoogle Scholar
  35. 35.
    Przedborski S, Tieu K, Perier C, Vila M (2004) MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36(4):375–379CrossRefGoogle Scholar
  36. 36.
    Kahle PJ, Waak J, Gasser T (2009) DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic Biol Med 47(10):1354–1361CrossRefGoogle Scholar
  37. 37.
    Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1(8649):1269CrossRefGoogle Scholar
  38. 38.
    Batlevi Y, La Spada AR (2011) Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiol Dis 43(1):46–51CrossRefGoogle Scholar
  39. 39.
    Mbefo MK, Paleologou KE, Boucharaba A, Oueslati A, Schell H, Fournier M et al (2010) Phosphorylation of synucleins by members of the Polo-like kinase family. J Biol Chem 285(4):2807–2822CrossRefGoogle Scholar
  40. 40.
    Inglis KJ, Chereau D, Brigham EF, Chiou SS, Schobel S, Frigon NL et al (2009) Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem 284(5):2598–2602CrossRefGoogle Scholar
  41. 41.
    Bergeron M, Motter R, Tanaka P, Fauss D, Babcock M, Chiou SS et al (2014) In vivo modulation of polo-like kinases supports a key role for PLK2 in Ser129 alpha-synuclein phosphorylation in mouse brain. Neuroscience 256:72–82CrossRefGoogle Scholar
  42. 42.
    Oueslati A, Schneider BL, Aebischer P, Lashuel HA (2013) Polo-like kinase 2 regulates selective autophagic alpha-synuclein clearance and suppresses its toxicity in vivo. Proc Natl Acad Sci USA 110(41):E3945–E3954CrossRefGoogle Scholar
  43. 43.
    Li J, Ma W, Wang PY, Hurley PJ, Bunz F, Hwang PM (2014) Polo-like kinase 2 activates an antioxidant pathway to promote the survival of cells with mitochondrial dysfunction. Free Radic Biol Med. 73:270–277CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neurodegenerative Diseases Group, Neurosciences DivisionBiocruces Bizkaia Health Research InstituteBarakaldoSpain
  2. 2.Neurosciences DivisionCenter for Applied Medical Research (CIMA)PamplonaSpain
  3. 3.Idisna HRIPamplonaSpain
  4. 4.Neurology SectionBiomedical CenterGranadaSpain
  5. 5.Neurology DepartmentClinica Universidad de NavarraPamplonaSpain

Personalised recommendations