Skip to main content

Advertisement

SpringerLink
Log in

Cinnamic Acid Protects the Nigrostriatum in a Mouse Model of Parkinson’s Disease via Peroxisome Proliferator-Activated Receptorα

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD) is the second most common devastating human neurodegenerative disorder and despite intense investigation, no effective therapy is available for PD. Cinnamic acid, a naturally occurring aromatic fatty acid of low toxicity, is a precursor for the synthesis of a huge number of plant substances. This study highlights the neuroprotective effect of cinnamic acid in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Oral administration of cinnamic acid protected tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra pars compacta (SNpc) and TH fibers in the striatum of MPTP-insulted mice. Accordingly, oral cinnamic acid also normalized striatal neurotransmitters and improved locomotor activities in MPTP-intoxicated mice. While investigating mechanisms, we found that cinnamic acid induced the activation of peroxisome proliferator-activated receptor α (PPARα), but not PPARβ, in primary mouse astrocytes. Cinnamic acid mediated protection of the nigrostriatal system and locomotor activities in WT and PPARβ (–/–), but not PPARα (–/–) mice from MPTP intoxication suggests that cinnamic acid requires the involvement of PPARα in protecting dopaminergic neurons in this model of PD. This study delineates a new function of cinnamic acid in protecting dopaminergic neurons via PPARα that could be beneficial for PD.

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

Similar content being viewed by others

References

  1. Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA (2012) Parkinson’s disease. Subcell Biochem 65:389–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539:180–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Postuma RB, Berg D, Adler CH, Bloem BR, Chan P, Deuschl G, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Oertel W, Olanow CW, Poewe W, Stern M (2016) The new definition and diagnostic criteria of Parkinson’s disease. Lancet Neurol 15:546–548

    Article  PubMed  Google Scholar 

  4. Opara JA, Brola W, Leonardi M, Blaszczyk B (2012) Quality of life in Parkinson’s disease. J Med Life 5:375–381

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Schrag A, Choudhury M, Kaski D, Gallagher DA (2015) Why do patients with Parkinson’s disease fall? A cross-sectional analysis of possible causes of falls. NPJ Parkinsons Dis 1:15011

    Article  PubMed  PubMed Central  Google Scholar 

  6. Diederich NJ, Fenelon G, Stebbins G, Goetz CG (2009) Hallucinations in Parkinson disease. Nat Rev Neurol 5:331–342

    Article  CAS  PubMed  Google Scholar 

  7. Hindle JV (2010) Ageing, neurodegeneration and Parkinson’s disease. Age Ageing 39:156–161

    Article  PubMed  Google Scholar 

  8. Seibyl JP, Marek KL, Quinlan D, Sheff K, Zoghbi S, Zea-Ponce Y, Baldwin RM, Fussell B, Smith EO, Charney DS, van Dyck C et al (1995) Decreased single-photon emission computed tomographic [123I]beta-CIT striatal uptake correlates with symptom severity in Parkinson’s disease. Ann Neurol 38:589–598

    Article  CAS  PubMed  Google Scholar 

  9. Ellis JM, Fell MJ (2017) Current approaches to the treatment of Parkinson’s Disease. Bioorg Med Chem Lett 27:4247–4255

    Article  CAS  PubMed  Google Scholar 

  10. Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A (2013) The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord 28:311–318

    Article  PubMed  Google Scholar 

  11. Adisakwattana S (2017) Cinnamic acid and its derivatives: mechanisms for prevention and management of diabetes and its complications. Nutrients 9:163

    Article  CAS  PubMed Central  Google Scholar 

  12. Liu L, Hudgins WR, Shack S, Yin MQ, Samid D (1995) Cinnamic acid: a natural product with potential use in cancer intervention. Int J Cancer 62:345–350

    Article  CAS  PubMed  Google Scholar 

  13. Guo JP, Yu S, McGeer PL (2010) Simple in vitro assays to identify amyloid-beta aggregation blockers for Alzheimer’s disease therapy. J Alzheimers Dis 19:1359–1370

    Article  CAS  PubMed  Google Scholar 

  14. Hemmati AA, Alboghobeish S, Ahangarpour A (2018) Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice. Korean J Physiol Pharmacol 22:257–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Chandra G, Roy A, Rangasamy SB, Pahan K (2016) Induction of adaptive immunity leads to nigrostriatal disease progression in MPTP mouse model of Parkinson’s disease. J Immunol 198:4312–4326

    Article  CAS  Google Scholar 

  17. Khasnavis S, Pahan K (2014) Cinnamon treatment upregulates neuroprotective proteins Parkin and DJ-1 and protects dopaminergic neurons in a mouse model of Parkinson’s disease. J Neuroimmune Pharmacol 9:569–581

    Article  PubMed  PubMed Central  Google Scholar 

  18. Khasnavis S, Roy A, Ghosh S, Watson R, Pahan K (2014) Protection of dopaminergic neurons in a mouse model of Parkinson’s disease by a physically-modified saline containing charge-stabilized nanobubbles. J Neuroimmune Pharmacol 9:218–232

    Article  PubMed  Google Scholar 

  19. Varghese F, Bukhari AB, Malhotra R, De A (2014) IHC profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9:e96801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K (2009) Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurosci 29:13543–13556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 104:18754–18759

    Article  PubMed  PubMed Central  Google Scholar 

  22. Pahan K, Jana M, Liu X, Taylor BS, Wood C, Fischer SM (2002) Gemfibrozil, a lipid-lowering drug, inhibits the induction of nitric-oxide synthase in human astrocytes. J Biol Chem 277:45984–45991

    Article  CAS  PubMed  Google Scholar 

  23. Roy A, Kundu M, Jana M, Mishra RK, Yung Y, Luan CH, Gonzalez FJ, Pahan K (2016) Identification and characterization of PPARalpha ligands in the hippocampus. Nat Chem Biol 12:1075–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Luchtman DW, Shao D, Song C (2009) Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson’s disease. Physiol Behav 98:130–138

    Article  CAS  PubMed  Google Scholar 

  25. Roy A, Pahan K (2009) Gemfibrozil, stretching arms beyond lipid lowering. Immunopharmacol Immunotoxicol 31:339–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Roy A, Pahan K (2015) PPARalpha signaling in the hippocampus: crosstalk between fat and memory. J Neuroimmune Pharmacol 10:30–34

    Article  PubMed  PubMed Central  Google Scholar 

  27. Corbett GT, Gonzalez FJ, Pahan K (2015) Activation of peroxisome proliferator-activated receptor alpha stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci USA 112:8445–8450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ghosh A, Pahan K (2016) PPARalpha in lysosomal biogenesis: a perspective. Pharmacol Res 103:144–148

    Article  CAS  PubMed  Google Scholar 

  29. Roy A, Jana M, Corbett GT, Ramaswamy S, Kordower JH, Gonzalez FJ, Pahan K (2013) Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor alpha. Cell Rep 4:724–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK, Luan CH, Gonzalez FJ, Pahan K (2015) HMG-CoA reductase inhibitors bind to PPARα to upregulate neurotrophin expression in the brain and improve memory in mice. Cell Metab 22:253–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fahn S (1999) Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. Arch Neurol 56:529–535

    Article  CAS  PubMed  Google Scholar 

  32. Hickey P, Stacy M (2016) Deep brain stimulation: a paradigm shifting approach to treat Parkinson’s disease. Front Neurosci 10:173

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kwiatek-Majkusiak J, Geremek M, Koziorowski D, Tomasiuk R, Szlufik S, Friedman A (2018) Higher serum levels of pro-hepcidin in patients with Parkinson’s disease treated with deep brain stimulation. Neurosci Lett. https://doi.org/10.1016/j.neulet.2018.06.031

    Article  PubMed  Google Scholar 

  34. Xu Y, Yang J, Shang H (2016) Meta-analysis of risk factors for Parkinson’s disease dementia. Transl Neurodegener 5:11

    Article  PubMed  PubMed Central  Google Scholar 

  35. Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR (2015) Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend 146:30–38

    Article  CAS  PubMed  Google Scholar 

  36. Duell EJ, Millikan RC, Savitz DA, Newman B, Smith JC, Schell MJ, Sandler DP (2000) A population-based case-control study of farming and breast cancer in North Carolina. Epidemiology 11:523–531

    Article  CAS  PubMed  Google Scholar 

  37. Bohingamu Mudiyanselage S, Watts JJ, Abimanyi-Ochom J, Lane L, Murphy AT, Morris ME, Iansek R (2017) Cost of living with Parkinson’s disease over 12 months in Australia: a prospective cohort study. Parkinsons Dis 2017:5932675

    PubMed  PubMed Central  Google Scholar 

  38. Salvador VH, Lima RB, dos Santos WD, Soares AR, Bohm PA, Marchiosi R, Ferrarese Mde L, Ferrarese-Filho O (2013) Cinnamic acid increases lignin production and inhibits soybean root growth. PLoS ONE 8:e69105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mangelsdorf DJ, Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83:841–850

    Article  CAS  PubMed  Google Scholar 

  40. Dunning KR, Anastasi MR, Zhang VJ, Russell DL, Robker RL (2014) Regulation of fatty acid oxidation in mouse cumulus-oocyte complexes during maturation and modulation by PPAR agonists. PLoS ONE 9:e87327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cimini A, Ceru MP (2008) Emerging roles of peroxisome proliferator-activated receptors (PPARs) in the regulation of neural stem cells proliferation and differentiation. Stem Cell Rev 4:293–303

    Article  CAS  PubMed  Google Scholar 

  42. Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470–477

    Article  CAS  PubMed  Google Scholar 

  43. Straus DS, Glass CK (2007) Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 28:551–558

    Article  CAS  PubMed  Google Scholar 

  44. Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88:494–501

    Article  CAS  PubMed  Google Scholar 

  45. Feinstein DL (2003) Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease. Diabetes Technol Ther 5:67–73

    Article  CAS  PubMed  Google Scholar 

  46. Toyama T, Nakamura H, Harano Y, Yamauchi N, Morita A, Kirishima T, Minami M, Itoh Y, Okanoue T (2004) PPARα ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem Biophys Res Commun 324:697–704

    Article  CAS  PubMed  Google Scholar 

  47. Yang Y, Gocke AR, Lovett-Racke A, Drew PD, Racke MK (2008) PPAR alpha regulation of the immune response and autoimmune encephalomyelitis. PPAR Res. https://doi.org/10.1155/2008/546753

    Article  PubMed  PubMed Central  Google Scholar 

  48. Skoczynska A, Dobosz T, Poreba R, Turczyn B, Derkacz A, Zoledziewska M, Jonkisz A, Lebioda A (2005) The dependence of serum interleukin-6 level on PPAR-alpha polymorphism in men with coronary atherosclerosis. Eur J Intern Med 16:501–506

    Article  CAS  PubMed  Google Scholar 

  49. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3:461–491

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kim T, Yang Q (2013) Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. World J Cardiol 5:164–174

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hwang O (2013) Role of oxidative stress in Parkinson’s disease. Exp Neurobiol 22:11–17

    Article  PubMed  PubMed Central  Google Scholar 

  52. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:91

    PubMed  PubMed Central  Google Scholar 

  53. Rodriguez M, Morales I, Rodriguez-Sabate C, Sanchez A, Castro R, Brito JM, Sabate M (2014) The degeneration and replacement of dopamine cells in Parkinson’s disease: the role of aging. Front Neuroanat 8:80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bento-Abreu A, Tabernero A, Medina JM (2007) Peroxisome proliferator-activated receptor-alpha is required for the neurotrophic effect of oleic acid in neurons. J Neurochem 103:871–881

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a merit award from the Department of Veteran Affairs (1I01BX003033) and Grants (NS83054 and AG050431) from National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, USA

    Tim Prorok, Malabendu Jana, Dhruv Patel & Kalipada Pahan

  2. Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite 310, Chicago, IL, 60612, USA

    Tim Prorok, Malabendu Jana, Dhruv Patel & Kalipada Pahan

Authors
  1. Tim Prorok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malabendu Jana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dhruv Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kalipada Pahan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kalipada Pahan.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prorok, T., Jana, M., Patel, D. et al. Cinnamic Acid Protects the Nigrostriatum in a Mouse Model of Parkinson’s Disease via Peroxisome Proliferator-Activated Receptorα. Neurochem Res 44, 751–762 (2019). https://doi.org/10.1007/s11064-018-02705-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-02705-0

Keywords

Search

Navigation