Skip to main content

Advertisement

SpringerLink
Log in

Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson’s disease

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

l-Dopa continues to be the gold drug in Parkinson’s disease (PD) treatment from 1967. The failure to translate successful results from preclinical to clinical studies can be explained by the use of preclinical models which do not reflect what happens in the disease since these induce a rapid and extensive degeneration; for example, MPTP induces a severe Parkinsonism in only 3 days in humans contrasting with the slow degeneration and progression of PD. This study presents a new anatomy and develops preclinical model based on aminochrome which induces a slow and progressive dysfunction of dopaminergic neurons. The unilateral injection of aminochrome into rat striatum resulted in (1) contralateral rotation when the animals are stimulated with apomorphine; (2) absence of significant loss of tyrosine hydroxylase-positive neuronal elements both in substantia nigra and striatum; (3) cell shrinkage; (4) significant reduction of dopamine release; (5) significant increase in GABA release; (6) significant decrease in the number of monoaminergic presynaptic vesicles; (7) significant increase of dopamine concentration inside of monoaminergic vesicles; (8) significant increase of damaged mitochondria; (9) significant decrease of ATP level in the striatum (10) significant decrease in basal and maximal mitochondrial respiration. These results suggest that aminochrome induces dysfunction of dopaminergic neurons where the contralateral behavior can be explained by aminochrome-induced ATP decrease required both for anterograde transport of synaptic vesicles and dopamine release. Aminochrome could be implemented as a new model neurotoxin to study Parkinson’s disease.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Segura-Aguilar J, Muñoz P, Paris I (2016) Aminochrome as new preclinical model to find new pharmacological treatment that stop the development of Parkinson’s disease. Curr Med Chem 23:346–359. doi:10.2174/0929867323666151223094103

    Article  CAS  PubMed  Google Scholar 

  2. Lindholm D, Mäkelä J, Di Liberto V, Mudò G, Belluardo N, Eriksson O, Saarma M (2015) Current disease modifying approaches to treat Parkinson’s disease. Cell Mol Life Sci. doi:10.1007/s00018-015-2101-1

    PubMed  Google Scholar 

  3. Olanow Bartus RT, Volpicelli-Daley LA, Kordower JH (2015) Trophic factors for Parkinson’s disease: to live or let die. Mov Disord 30:1715–1724. doi:10.1002/mds.26426

    Article  PubMed  Google Scholar 

  4. Segura-Aguilar J, Kostrzewa RM (2015) Neurotoxin mechanisms and processes relevant to Parkinson’s disease: an update. Neurotox Res 27:328–354. doi:10.1007/s12640-015-9519-y

    Article  CAS  PubMed  Google Scholar 

  5. Segura-Aguilar J, Paris I, Muñoz P, Ferrari E, Zecca L, Zucca FA (2014) Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem 129:898–915. doi:10.1111/jnc.12686

    Article  CAS  PubMed  Google Scholar 

  6. Mullin S, Schapira A (2013) α-Synuclein and mitochondrial dysfunction in Parkinson’s disease. Mol Neurobiol 47:587–597. doi:10.1007/s12035-013-8394-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE (2013) α-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol 73:155–169. doi:10.1002/ana.23746

    Article  CAS  PubMed  Google Scholar 

  8. Ebrahimi-Fakhari D, Wahlster L, McLean PJ (2012) Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol 124:153–172. doi:10.1007/s00401-012-1004-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mercado G, Valdés P, Hetz C (2013) An ERcentric view of Parkinson’s disease. Trends Mol Med 19:165–175. doi:10.1016/j.molmed.2012.12.005

    Article  CAS  PubMed  Google Scholar 

  10. Aguirre P, Urrutia P, Tapia V, Villa M, Paris I, Segura-Aguilar J, Núñez MT (2012) The dopamine metabolite aminochrome inhibits mitochondrial complex I and modifies the expression of iron transporters DMT1 and FPN1. Biometals 25:795–803. doi:10.1007/s10534-012-9525-y

    Article  CAS  PubMed  Google Scholar 

  11. Zafar KS, Siegel D, Ross D (2006) A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. Mol Pharmacol 70:1079–1086. doi:10.1124/mol.106.024703

    Article  CAS  PubMed  Google Scholar 

  12. Huenchuguala S, Muñoz P, Zavala P, Villa M, Cuevas C, Ahumada U, Graumann R, Nore BF, Couve E, Mannervik B, Paris I, Segura-Aguilar J (2014) Glutathione transferase mu 2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction. Autophagy 10:618–630. doi:10.4161/auto.27720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Arriagada C, Paris I, Sanchez de las Matas MJ, Martinez-Alvarado P, Cardenas S, Castañeda P, Graumann R, Perez-Pastene C, Olea-Azar C, Couve E, Herrero MT, Caviedes P, Segura-Aguilar J (2004) On the neurotoxicity mechanism of leukoaminochrome o-semiquinone radical derived from dopamine oxidation: mitochondria damage, necrosis, and hydroxyl radical formation. Neurobiol Dis 16:468–477. doi:10.1016/j.nbd.2004.03.014

    Article  CAS  PubMed  Google Scholar 

  14. Xiong R, Siegel D, Ross D (2014) Quinone-induced protein handling changes: implications for major protein handling systems in quinone-mediated toxicity. Toxicol Appl Pharmacol 280:285–295. doi:10.1016/j.taap.2014.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Muñoz P, Cardenas S, Huenchuguala S, Briceño A, Couve E, Paris I, Segura-Aguilar J (2015) DT Diaphorase prevents aminochrome-induced alpha-synuclein oligomer formation and neurotoxicity. Toxicol Sci 145:37–47. doi:10.1093/toxsci/kfv016

    Article  PubMed  PubMed Central  Google Scholar 

  16. Segura-Aguilar J, Lind C (1989) On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine: prevention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase. Chem Biol Interact 72:309–324. doi:10.1016/0009-2797(89)90006-9

    Article  CAS  PubMed  Google Scholar 

  17. Segura-Aguilar J, Diaz-Veliz G, Mora S, Herrera-Marschitz M (2002) Inhibition of DT-diaphorase is a requirement for Mn(III) to produce a 6-OH-dopamine like rotational behaviour. Neurotox Res 4:127–131. doi:10.1080/10298420290015926

    Article  CAS  PubMed  Google Scholar 

  18. Sotomayor R, Forray MI, Gysling K (2005) Acute morphine administration increases extracellular DA levels in the rat lateral septum by decreasing the GABAergic inhibitory tone in the ventral tegmental area. J Neurosci Res 81:132–139. doi:10.1002/jnr.20537

    Article  CAS  PubMed  Google Scholar 

  19. Fried N, Moffat C, Seifert E, Oshinsky M (2014) Functional mitochondrial analysis in acute brain sections from adult rats reveals mitochondrial dysfunction in a rat model of migraine. Am J Physiol Cell Physiol 307:C1017–C1030. doi:10.1152/ajpcell.00332.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Herrera-Marschitz M, Arbuthnott G, Ungerstedt U (2010) The rotational model and microdialysis: significance for dopamine signalling, clinical studies, and beyond. Prog Neurobiol 90:176–189. doi:10.1016/j.pneurobio.2009.01.005

    Article  CAS  PubMed  Google Scholar 

  21. Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164:1357–1391. doi:10.1111/j.1476-5381.2011.01426.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Penttinen AM, Suleymanova I, Albert K, Anttila J, Voutilainen MH, Airavaara M (2016) Characterization of a new low-dose 6-hydroxydopamine model of Parkinson’s disease in rat. J Neurosci Res 94:318–328. doi:10.1002/jnr.23708

    Article  CAS  PubMed  Google Scholar 

  23. di Michele F, Luchetti S, Bernardi G, Romeo E, Longone P (2013) Neurosteroid and neurotransmitter alterations in Parkinson’s disease. Front Neuroendocrinol 34:132–142. doi:10.1016/j.yfrne

    Article  PubMed  Google Scholar 

  24. Paris I, Perez-Pastene C, Cardenas S, Iturriaga-Vasquez P, Muñoz P, Couve E, Caviedes P, Segura-Aguilar J (2010) Aminochrome induces disruption of actin, alpha-, and beta-tubulin cytoskeleton networks in substantia-nigra-derived cell line. Neurotox Res 18:82–92. doi:10.1007/s12640-009-9148-4

    Article  PubMed  Google Scholar 

  25. Briceño A, Muñoz P, Brito P, Huenchuguala S, Segura-Aguilar J, Paris IB (2015) Aminochrome toxicity is mediated by inhibition of microtubules polymerization through the formation of adducts with tubulin. Neorotox Res. doi:10.1007/s12640-015-9560-x

    Google Scholar 

  26. Divakaruni AS, Paradyse A, Ferrick DA, Murphy AN, Jastroch M (2014) Analysis and interpretation of microplate-based oxygen consumption and pH data. Methods Enzymol 547:309–354. doi:10.1016/B978-0-12-801415-8.00016-3

    Article  CAS  PubMed  Google Scholar 

  27. Muñoz P, Paris I, Sanders LH, Greenamyre JT, Segura-Aguilar J (2012) Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity. Biochim Biophys Acta 1822:1125–1136. doi:10.1016/j.bbadis.2012.03.010

    Article  PubMed  Google Scholar 

  28. Paris I, Muñoz P, Huenchuguala S, Couve E, Sanders LH, Greenamyre JT, Caviedes P, Segura-Aguilar J (2011) Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line. Toxicol Sci 121:376–388. doi:10.1093/toxsci/kfr060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Muñoz P, Huenchuguala S, Paris I, Segura-Aguilar J (2012) Dopamine oxidation and autophagy. Parkinsons Dis 2012:920953. doi:10.1155/2012/920953

    PubMed  PubMed Central  Google Scholar 

  30. Segura-Aguila J, Metodiewa D, Welch CJ (1998) Metabolic activation of dopamine o-quinones to o-semiquinones by NADPH cytochrome P450 reductase may play an important role in oxidative stress and apoptotic effects. Biochim Biophys Acta 1381:1–6. doi:10.1016/S0304-4165(98)00036-1

    Article  Google Scholar 

  31. Schultzberg M, Segura-Aguilar J, Lind C (1988) Distribution of DT diaphorase in the rat brain: biochemical and immunohistochemical studies. Neuroscience 27:763–776. doi:10.1016/0306-4522(88)90181-9

    Article  CAS  PubMed  Google Scholar 

  32. Lozano J, Muñoz P, Nore BF, Ledoux S, Segura-Aguilar J (2010) Stable expression of short interfering RNA for DT-diaphorase induces neurotoxicity. Chem Res Toxicol 23:1492–1496. doi:10.1021/tx100182a

    Article  CAS  PubMed  Google Scholar 

  33. Segura-Aguilar J, Baez S, Widersten M, Welch CJ, Mannervik B (1997) Human class Mu glutathione transferases, in particular isoenzyme M2-2, catalyze detoxication of the dopamine metabolite aminochrome. J Biol Chem 272:5727–5731. doi:10.1074/jbc.272.9.5727

    Article  CAS  PubMed  Google Scholar 

  34. Baez S, Segura-Aguilar J, Widersten M, Johansson AS, Mannervik B (1997) Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem J 324:25–28. doi:10.1042/bj3240025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dagnino-Subiabre A, Cassels BK, Baez S, Johansson AS, Mannervik B, Segura-Aguilar J (2000) Glutathione transferase M2-2 catalyzes conjugation of dopamine and dopa o-quinones. Biochem Biophys Res Commun 274:32–36. doi:10.1006/bbrc.2000.3087

    Article  CAS  PubMed  Google Scholar 

  36. Carstam R, Brinck C, Hindemith-Augustsson A, Rorsman H, Rosengren E (1991) The neuromelanin of the human substantia nigra. Biochim Biophys Acta 1097:152–160

    Article  CAS  PubMed  Google Scholar 

  37. Rosengren E, Linder-Eliasson E, Carlsson A (1985) Detection of 5-S-cysteinyldopamine in human brain. J Neural Transm 63:247–253. doi:10.1007/BF01252029

    Article  CAS  PubMed  Google Scholar 

  38. Cuevas C, Huenchuguala S, Muñoz P, Villa M, Paris I, Mannervik B, Segura-Aguilar J (2015) Glutathione transferase-M2-2 secreted from glioblastoma cell protects SH-SY5Y cells from aminochrome neurotoxicity. Neurotox Res 27(217–228):429. doi:10.1007/s12640-014-9500-1

    Google Scholar 

  39. Segura-Aguilar J (2015) A new mechanism for protection of dopaminergic neurons mediated by astrocytes. Neural Regen Res 10:1225–1227. doi:10.4103/1673-5374.162750

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cazorla M, Kang UJ, Kellendonk C (2015) Balancing the basal ganglia circuitry: a possible new role for dopamine D2 receptors in health and disease. Mov Disord 30:895–903. doi:10.1002/mds.26282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Touchette JC, Breckenridge JM, Wilken GH, Macarthur H (2015) Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons. Neurosci Lett 612:178–184. doi:10.1016/j.neulet.2015.12.028

    Article  PubMed  Google Scholar 

  42. Ochs SD, Westfall TC, Macarthur H (2005) The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection. J Neurosci Methods 142:201–208. doi:10.1016/j.jneumeth.2004.08.010

    Article  CAS  PubMed  Google Scholar 

  43. Segura-Aguilar J, Paris I, Muñoz P (2016) The need of a new and more physiological preclinical model for Parkinson’s disease. Cell Mol Life Sci. doi:10.1007/s00018-016-2140-2

    Google Scholar 

Download references

Acknowledgments

This work was supported by FONDECYT # 1100165 (JSA), University of Chile ENL014/14 (JSA); ECOS-CONICYT # C10S02 (JSA, RR-V). FONDECYT # 1120443, FONDAP # 15150012 (CC) and FONDECYT postdoctoral fellowship # 3140458 (FJ)

Author information

Authors and Affiliations

  1. Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile

    Andrea Herrera, Patricia Muñoz, Irmgard Paris, Gabriela Díaz-Veliz, Sergio Mora & Juan Segura-Aguilar

  2. Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Geroscience Center for Brain Health and Metabolism, , Santiago, Chile

    Cesar Cardenas & Fabián Jaña

  3. Departamento de Ciencias Básicas, Universidad Santo Tomas, Viña del Mar, Chile

    Irmgard Paris

  4. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

    Jose Inzunza

  5. Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Kjell Hultenby

  6. INSERM U1127, Paris, France

    Rita Raisman-Vozari

  7. Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile

    Katia Gysling & Jorge Abarca

  8. Department of Translational Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands

    Andrea Herrera & Harry W. M. Steinbusch

Authors
  1. Andrea Herrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irmgard Paris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriela Díaz-Veliz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergio Mora
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose Inzunza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kjell Hultenby
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cesar Cardenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fabián Jaña
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rita Raisman-Vozari
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Katia Gysling
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jorge Abarca
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Harry W. M. Steinbusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Juan Segura-Aguilar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan Segura-Aguilar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Herrera, A., Muñoz, P., Paris, I. et al. Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson’s disease. Cell. Mol. Life Sci. 73, 3583–3597 (2016). https://doi.org/10.1007/s00018-016-2182-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-016-2182-5

Keywords

Search

Navigation