Skip to main content

Neuroprotective and Anti-inflammatory Properties of a Coffee Component in the MPTP Model of Parkinson’s Disease

Neurotherapeutics volume 10, pages 143–153 (2013)Cite this article

Abstract

Consumption of coffee is associated with reduced risk of Parkinson’s disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP+-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

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

References

  1. Jenner P. Oxidative stress in Parkinson's disease. Ann Neurol 2003;53 Suppl 3:S26–36; discussion S36–28.

    PubMed  Article  CAS  Google Scholar 

  2. Hirsch EC, Hunot S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 2009;8:382–397.

    PubMed  Article  CAS  Google Scholar 

  3. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol 2010;6:193–201.

    PubMed  Article  Google Scholar 

  4. Parker WD, Jr., Swerdlow RH. Mitochondrial dysfunction in idiopathic Parkinson disease. Am J Hum Genet 1998;62:758–762.

    PubMed  Article  Google Scholar 

  5. Przedborski S, Jackson-Lewis V. Mechanisms of MPTP toxicity. Mov Disord 1998;13 Suppl 1:35–38.

    PubMed  Google Scholar 

  6. Lee KW, Chen W, Junn E, et al. Enhanced phosphatase activity attenuates alpha-Synucleinopathy in a mouse model. J Neurosci 2011;31:6963–6971.

    PubMed  Article  CAS  Google Scholar 

  7. Ross GW, Abbott RD, Petrovitch H, et al. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA 2000;283:2674–2679.

    PubMed  Article  CAS  Google Scholar 

  8. Ascherio A, Zhang SM, Hernan MA, et al. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann Neurol 2001;50:56–63.

    PubMed  Article  CAS  Google Scholar 

  9. Ascherio A, Weisskopf MG, O'Reilly EJ, et al. Coffee consumption, gender, and Parkinson's disease mortality in the cancer prevention study II cohort: the modifying effects of estrogen. Am J Epidemiol 2004;160:977–984.

    PubMed  Article  Google Scholar 

  10. Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A. Caffeine exposure and the risk of Parkinson's disease: a systematic review and meta-analysis of observational studies. J Alzheimers Dis 2010;20 Suppl 1:S221–238.

    PubMed  CAS  Google Scholar 

  11. Freeman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012;366:1891–1904.

    Article  Google Scholar 

  12. Trinh K, Andrews L, Krause J, et al. Decaffeinated coffee and nicotine-free tobacco provide neuroprotection in Drosophila models of Parkinson's disease through an NRF2-dependent mechanism. J Neurosci 2010;30:5525–5532.

    PubMed  Article  CAS  Google Scholar 

  13. Lee KW, Zhao X, Im JY, et al. Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. PLoS One 2012;7:e29935.

    PubMed  Article  CAS  Google Scholar 

  14. West MJ, Slomianka L, Gundersen HJ. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec 1991;231:482–497.

    PubMed  Article  CAS  Google Scholar 

  15. Sonsalla PK, Youngster SK, Kindt MV, Heikkila RE. Characteristics of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse. J Pharmacol Exp Ther 1987;242:850–857.

    PubMed  CAS  Google Scholar 

  16. Alfinito PD, Wang SP, Manzino L, et al. Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively. J Neurosci 2003;23:10982–10987.

    PubMed  CAS  Google Scholar 

  17. Kim D, Joe CO, Han PL. Extracellular and intracellular glutathione protects astrocytes from Zn2 + −induced cell death. Neuroreport 2003;14:187–190.

    PubMed  Article  CAS  Google Scholar 

  18. Lee EJ, Woo MS, Moon PG, et al. Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol 2010;185:615–623.

    PubMed  Article  CAS  Google Scholar 

  19. Liberatore GT, Jackson-Lewis V, Vukosavic S, et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999;5:1403–1409.

    PubMed  Article  CAS  Google Scholar 

  20. Wu DC, Jackson-Lewis V, Vila M, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002;22:1763–1771.

    PubMed  CAS  Google Scholar 

  21. Vila M, Jackson-Lewis V, Guegan C, et al. The role of glial cells in Parkinson's disease. Curr Opin Neurol 2001;14:483–489.

    PubMed  Article  CAS  Google Scholar 

  22. Zolnierowicz S. Type 2A protein phosphatase, the complex regulator of numerous signaling pathways. Biochem Pharmacol 2000;60:1225–1235.

    PubMed  Article  CAS  Google Scholar 

  23. Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001;353:417–439.

    PubMed  Article  CAS  Google Scholar 

  24. Garcia A, Cayla X, Guergnon J, et al. Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochimie 2003;85:721–726.

    PubMed  Article  CAS  Google Scholar 

  25. Virshup DM, Shenolikar S. From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 2009;33:537–545.

    PubMed  Article  CAS  Google Scholar 

  26. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007;8:57–69.

    PubMed  Article  CAS  Google Scholar 

  27. Przedborski S, Tieu K, Perier C, Vila M. MPTP as a mitochondrial neurotoxic model of Parkinson's disease. J Bioenerg Biomembr 2004;36:375–379.

    PubMed  Article  CAS  Google Scholar 

  28. Przedborski S, Ischiropoulos H. Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson's disease. Antioxid Redox Signal 2005;7:685–693.

    PubMed  Article  CAS  Google Scholar 

  29. Cassarino DS, Fall CP, Swerdlow RH, et al. Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease. Biochim Biophys Acta 1997;1362:77–86.

    PubMed  Article  CAS  Google Scholar 

  30. Hsu LJ, Sagara Y, Arroyo A, et al. Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 2000;157:401–410.

    PubMed  Article  CAS  Google Scholar 

  31. Junn E, Mouradian MM. Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett 2002;320:146–150.

    PubMed  Article  CAS  Google Scholar 

  32. Whisler RL, Goyette MA, Grants IS, Newhouse YG. Sublethal levels of oxidant stress stimulate multiple serine/threonine kinases and suppress protein phosphatases in Jurkat T cells. Arch Biochem Biophys 1995;319:23–35.

    PubMed  Article  CAS  Google Scholar 

  33. Rao RK, Clayton LW. Regulation of protein phosphatase 2A by hydrogen peroxide and glutathionylation. Biochem Biophys Res Commun 2002;293:610–616.

    PubMed  Article  CAS  Google Scholar 

  34. Kim HS, Song MC, Kwak IH, Park TJ, Lim IK. Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence. J Biol Chem 2003;278:37497–37510.

    PubMed  Article  CAS  Google Scholar 

  35. Su B, Wang X, Lee HG, et al. Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci Lett 2010;468:267–271.

    PubMed  Article  CAS  Google Scholar 

  36. Shanley TP, Vasi N, Denenberg A, Wong HR. The serine/threonine phosphatase, PP2A: endogenous regulator of inflammatory cell signaling. J Immunol 2001;166:966–972.

    PubMed  CAS  Google Scholar 

  37. Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG. Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci 2005;118:3523–3530.

    PubMed  Article  CAS  Google Scholar 

  38. Lou H, Montoya SE, Alerte TN, et al. Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. J Biol Chem 2010;285:17648–17661.

    PubMed  Article  CAS  Google Scholar 

  39. Sontag E, Hladik C, Montgomery L, et al. Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol 2004;63:1080–1091.

    PubMed  CAS  Google Scholar 

  40. Eskelinen MH, Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer's disease. J Alzheimers Dis 2010;20 Suppl 1:S167–174.

    PubMed  CAS  Google Scholar 

  41. Voronkov M, Braithwaite SP, Stock JB. Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease. Future Med Chem 2011;3:821–833.

    PubMed  Article  CAS  Google Scholar 

  42. Braithwaite SP, Voronkov M, Stock JB, Mouradian MM. Targeting phosphatases as the next generation of disease modifying therapeutics for Parkinson's disease. Neurochem Int 2012;61(6):899–906.

    PubMed  Article  CAS  Google Scholar 

  43. Chen JF, Xu K, Petzer JP, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci 2001;21:RC143.

    PubMed  CAS  Google Scholar 

  44. Simon DK, Swearingen CJ, Hauser RA, et al. Caffeine and progression of Parkinson disease. Clin Neuropharmacol 2008;31:189–196.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from Signum Biosciences and NIH grant AT006868 to M.M.M., who is the William Dow Lovett Professor of Neurology and is also supported by NIH grants NS059869 and NS073994. E.J. is supported by NIH grant NS070898. J.B.S. is supported in part by a grant from the American Parkinson Disease Association and by NIH grant AT006868.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Author notes

  1. Kang-Woo Lee

    Present address: Medical Research Division, Acupuncture, Moxibustion & Meridian Research Group, Korea Institute of Oriental Medicine, Daejeon, South Korea, 305-811

  2. Steven P. Braithwaite

    Present address: Circuit Therapeutics, Inc., Menlo Park, CA, 94025, USA

Affiliations

  1. Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 683 Hoes Lane West, Room 180, Piscataway, NJ, 08854, USA

    Kang-Woo Lee, Joo-Young Im, Jong-Min Woo, Hilary Grosso, Patricia K. Sonsalla, Eunsung Junn & M. Maral Mouradian

  2. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA

    Yoon-Seong Kim & Ana Clara Cristovao

  3. Health Sciences Research Center, University of Beira Interior, Covilhã, Portugal

    Ana Clara Cristovao

  4. Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA

    David S. Schuster, Marla M. Jalbut & Jeffry B. Stock

  5. Signum Biosciences, Inc., Monmouth Junction, NJ, 08852, USA

    Jose R. Fernandez, Michael Voronkov, Steven P. Braithwaite & Jeffry B. Stock

Authors
  1. Kang-Woo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joo-Young Im
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jong-Min Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hilary Grosso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoon-Seong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ana Clara Cristovao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patricia K. Sonsalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David S. Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marla M. Jalbut
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jose R. Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael Voronkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eunsung Junn
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Steven P. Braithwaite
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jeffry B. Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M. Maral Mouradian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Maral Mouradian.

Additional information

Kang-Woo Lee and Joo-Young Im contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 550 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, KW., Im, JY., Woo, JM. et al. Neuroprotective and Anti-inflammatory Properties of a Coffee Component in the MPTP Model of Parkinson’s Disease. Neurotherapeutics 10, 143–153 (2013). https://doi.org/10.1007/s13311-012-0165-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13311-012-0165-2

Keywords

  • Eicosanoyl-5-hydroxytryptamide
  • Neuroprotection
  • Anti-inflammatory
  • Antioxidant
  • Microglia
  • Astrocytes