, Volume 26, Issue 2, pp 349–360 | Cite as

Curcumin affords neuroprotection and inhibits α-synuclein aggregation in lipopolysaccharide-induced Parkinson’s disease model

  • Neha Sharma
  • Bimla NehruEmail author
Original Article


Parkinson’s disease (PD) pathology is characterized by the abnormal accumulation and aggregation of the pre-synaptic protein α-synuclein in the dopaminergic neurons as Lewy bodies (LBs). Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains obscure. Therefore, the present study was designed to understand such concealed mechanisms behind neuroprotective effects of curcumin. An animal model of PD was established by injecting lipopolysaccharide (LPS, 5 µg/5 µl PBS) into the substantia nigra (SN) of rats which was followed by curcumin administration (40 mg/kg b.wt (i.p.)) daily for a period of 21 days. Modulatory functions of curcumin were evident from the inhibition of astrocytic activation (GFAP) by immunofluorescence and NADPH oxidase complex activation by RT-PCR. Curcumin supplementation prevented the LPS-induced upregulation in the protein activity of transcription factor NFκB, proinflammatory cytokines (TNF-α, IL-1β, and IL-1α), inducible nitric oxide synthase (iNOS) as well as the regulating molecules of the intrinsic apoptotic pathway (Bax, Bcl-2, Caspase 3 and Caspase 9) by ELISA. Curcumin also resulted in significant improvement in the glutathione system (GSH, GSSG and redox ratio) and prevented iron deposition in the dopaminergic neurons as depicted from atomic absorption spectroscopy (AAS) and Prussian blue staining, respectively. Curcumin also prevented α-synuclein aggregates in the dopaminergic neurons as observed from gene as well as protein activity of α-synuclein using RT-PCR and IHC. Collectively, our results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.


α-Synuclein Astrocyte activation NADPH oxidase complex Neuroinflammation Glutathione homeostasis 



The study was carried out with the funds provided by Indian Council of Medical Research (ICMR) India (Grant no. 45/52/2013-PHA/BMS).

Compliance with ethical standards

Conflict of interest

The authors do not have any competing interests in the manuscript.


  1. Agbor GA, Oben JE, Ngogang JY, Xinxing C, Vinson JA (2005) Antioxidant capacity of some herbs/spices from Cameroon: a comparative study of two methods. J Agric Food Chem 53:6819–6824CrossRefPubMedGoogle Scholar
  2. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398PubMedGoogle Scholar
  3. Ahmad B, Lapidus LJ (2012) Curcumin prevents aggregation in α-synuclein by increasing reconfiguration rate. J Biol Chem 287:9193–9199CrossRefPubMedPubMedCentralGoogle Scholar
  4. Alvarez B, Demicheli V, Duran R, Trujillo M, Cervenansky C, Freeman BA, Radi R (2004) Inactivation of human Cu, Zn superoxide dismutase by peroxynitrite and formation of histidinyl radical. Free Radic Biol Med 37:813–822CrossRefPubMedGoogle Scholar
  5. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Rev Neurosci 5:S18–S25CrossRefGoogle Scholar
  6. Barreto GE, Gonzalez J, Capani F, Morales L (2011) Role of astrocytes in neurodegenerative diseases. In: Chang RCC (Ed) Neurodegenerative diseases–processes prevention protection and monitoring. Intechopen 485–486Google Scholar
  7. Behari M, Bhatnagar SP, Muthane U, Deo D (2002) Experiences of Parkinson’s disease in India. Lancet Neurol 1:258–262CrossRefPubMedGoogle Scholar
  8. Betarbet R, Sherer TB, Di Monte DA, Greenamyre JT (2002) Mechanistic approaches to Parkinson’s disease pathogenesis. Brain Pathol 12(4):499–510CrossRefPubMedGoogle Scholar
  9. Bharath et al (2002) Glutathione, iron and Parkinson’s disease. Biochem Pharmacol 64:1037–1048CrossRefPubMedGoogle Scholar
  10. Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE (2010) EGCG remodels mature α-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci USA 107:7710–7715CrossRefPubMedPubMedCentralGoogle Scholar
  11. Brown C, Neher JJ (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 41:242–247CrossRefPubMedGoogle Scholar
  12. Caruana M, Hogen T, Levin J, Hillmer A, Giese A, Vassallo N (2011) Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds. FEBS Lett 585:1113–1120CrossRefPubMedGoogle Scholar
  13. Cole GM, Lim GP, Yang F, Teter B, Begum A, Ma Q, Harris-White ME, Frautschy SA (2005) Prevention of Alzheimer’s disease: omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol Aging 26(1):133–136CrossRefPubMedGoogle Scholar
  14. Cole GM, Teter B, Frautschy SA (2007) Neuroprotective effects of curcumin. Adv Exp Med Biol 595:197–212CrossRefPubMedPubMedCentralGoogle Scholar
  15. Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320CrossRefPubMedGoogle Scholar
  16. Cookson MR (2005) Biochemistry of Parkinson’s disease. Annu Rev Biochem 74:29–52CrossRefPubMedGoogle Scholar
  17. Cristovao AC, Guhathakurta S, Bok E, Je G, Yoo SD, Choi DH, Kim YS (2012) NADPH oxidase 1 mediates alpha-synucleinopathy in Parkinson’s disease. J Neurosci 32:14465–14477CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dutta G, Zhang P, Liu B (2008) The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol 22:453–464CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ehrnhoefer DE et al (2008) EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15:558–566CrossRefPubMedGoogle Scholar
  20. Ellman GL (1959) Tissue sulphydryl groups. Arch Biochem Biophy 82:70–77CrossRefGoogle Scholar
  21. Esposito E, Cuzzocrea S (2009) Role of nitroso radicals as drug targets in circulatory shock. Br J Pharmacol 157(4):494–508CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ferreira N, Saraiva MJ, Almeida MR (2011) Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation. FEBS Lett 585:2424–2430CrossRefPubMedGoogle Scholar
  23. Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 75:787–809CrossRefPubMedGoogle Scholar
  24. Grzegorz CA, Magdalena C, Chalimoniuk M, Barbara G, Strosznajde JB (2007) Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation. J Neurosci Res 85:1694–1703CrossRefGoogle Scholar
  25. Hafner-Bratkovic I, Gaspersic J, Smid LM, Bresjanac M, Jerala R (2008) Curcumin binds to the α-helical intermediate and to the amyloid form of prion protein—a new mechanism for the inhibition of PrP(Sc) accumulation. J Neurochem 104:1553–1564CrossRefPubMedGoogle Scholar
  26. Hirsch EC, Vyas S, Hunot S (2012) Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord 18(1):S210–S212CrossRefPubMedGoogle Scholar
  27. Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13(1):24–34PubMedGoogle Scholar
  28. Jiao et al (2006) Iron chelation in the biological activity of curcumin. Free Radic Biol 40(7):1152–1160CrossRefGoogle Scholar
  29. Jiao et al (2009) Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 113(2):462–469CrossRefPubMedPubMedCentralGoogle Scholar
  30. Jouihan H (2012) Iron—Prussian blue reaction—Mallory’s method. Bio-protocol 2(13):e222. doi: 10.21769/BioProtoc.222 Google Scholar
  31. Kalivendi SV, Cunningham S, Kotamraju S, Joseph J, Hillard CJ, Kalyanaraman B (2004) α-Synuclein up-regulation and aggregation during MPP + -induced apoptosis in neuroblastoma cells—intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem 279(15):15240–15247CrossRefPubMedGoogle Scholar
  32. Karpinar DP et al (2009) Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson’s disease models. EMBO J 28:3256–3268CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kumar A, Chen SH, Kadiiska MB, Hong JS, Zielonka J, Kalyanaraman B, Mason RP (2014) Inducible nitric oxide synthase is key to peroxynitrite-mediated, LPS-induced protein radical Scheme 1. Role of NADPH oxidase and iNOS in Maneb- and paraquat-induced peroxynitrite-mediated protein radical formation Mol Neurobiol formation in murine microglial BV2 cells. Free Radic BiolMed 73:51–59CrossRefGoogle Scholar
  34. Kumar A, Leinisch F, Kadiiska M, Corbet J, Mason RP (2015) Formation and implications of alpha-synuclein radical in maneb- and paraquat-induced models of Parkinson’s disease. Mol Neurobiol 53(5):2983–2994CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lim GP, Chu T, Yang FS, Beech W, Frautschy SA, Cole GM (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21(21):8370–8377PubMedGoogle Scholar
  36. Liu Z, Yu Y, Li X, Ross CA, Smith WW (2011) Curcumin protects against A53T α-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol Res 63:439–444CrossRefPubMedGoogle Scholar
  37. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMedGoogle Scholar
  38. MacMillan-Crow LA, Crow JP, Thompson JA (1998) Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry 37:1613–1622CrossRefPubMedGoogle Scholar
  39. Mancuso C, Scapagnini G, Curro D, Stella AMG, De Marco C, Butterfield DA, Calabrese V (2007) Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci 12:1107–1123CrossRefPubMedGoogle Scholar
  40. Martin HL, Teismann P (2009) Glutathione—a review on its role and significance in Parkinson’s disease. FASEB J. 23(10):3263–3272CrossRefPubMedGoogle Scholar
  41. Martin ZS, Neugebauer V, Dineley KT, Kayed R, Zhang W, Reese LC, Taglialatela G (2012) α-Synuclein oligomers oppose long-term potentiation and impair memory through a calcineurin-dependent mechanism: relevance to human synucleopathic diseases. J Neurochem 120:440–452CrossRefPubMedGoogle Scholar
  42. Masuda M, Hasegawa M, Nonaka T, Oikawa T, Yonetani M, Yamaguchi Y, Kato K, Hisanaga S (2009) Goedert M (2009) Inhibition of α-synuclein fibril assembly by small molecules: analysis using epitope-specific antibodies. FEBS Lett 583:787–791CrossRefPubMedGoogle Scholar
  43. Olanow W (1992) An introduction to the free-radical hypothesis in Parkinsons-disease. Ann Neurol 32:S2–S9CrossRefPubMedGoogle Scholar
  44. Ono K, Yamada M (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro. J Neurochem 97:105–115CrossRefPubMedGoogle Scholar
  45. Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE (2008) Curcumin inhibits aggregation of α-synuclein. Acta Neuropathol 115:479–489CrossRefPubMedGoogle Scholar
  46. Paxinos GW, Watson C (2005) The rat brain in stereotaxic coordinates. Academic Press, OxfordGoogle Scholar
  47. Pearse AGE (1968) Histochemical, theoretical and applied, 3rd edn. Churchill Livingstone, London, p 660Google Scholar
  48. Pettifer KM, Jiang SC, Bau C, Ballerini P, D’Alimonte I, Werstiuk ES, Rathbone MP (2007) MPP + -induced cytotoxicity in neuroblastoma cells: antagonism and reversal by guanine. Purinergic signal 3(4):399–409CrossRefPubMedPubMedCentralGoogle Scholar
  49. Quilty MC, King AE, Gai WP, Pountney DL, West AK, Vickers JC, Dickson TC (2006) Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Exp Neurol 199:249–256CrossRefPubMedGoogle Scholar
  50. Raddassi K, Berthon B, Petit JF, Lemaire G (1994) Role of calcium in the activation of mouse peritoneal macrophages: induction of NO synthase by calcium ionophores and thapsigargin. Cell Immunol 153:443–455CrossRefPubMedGoogle Scholar
  51. Ragothaman M, Murgod UA, Gururaj G, Kumaraswamy SD, Muthane U (2003) Lower risk of Parkinson’s disease in an admixed population of European and Indian origins. Mov Disord 18:912–914CrossRefPubMedGoogle Scholar
  52. Rappold PM, Tieu K (2010) Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics 7(4):413–423CrossRefPubMedPubMedCentralGoogle Scholar
  53. Riederer P, Sofic P, Rrausch WD, Schmidt B, Reynolds GP (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52:515–520CrossRefPubMedGoogle Scholar
  54. Sekiyama K et al (2012) Neuroinflammation in Parkinson’s disease and related disorders: a lesson from genetically manipulated mouse models of α-synucleinopathies. Parkinson’s Dis. doi: 10.1155/2012/271732 Google Scholar
  55. Sharma N, Nehru B (2015) Characterization of the lipopolysaccharide induced model of Parkinson’s disease: role of oxidative stress and neuroinflammation. Neurochem Int 87:92–105CrossRefPubMedGoogle Scholar
  56. Sharma N, Kapoor M, Nehru B (2016) Apocyanin, NADPH oxidase inhibitor prevents lipopolysaccharide induced α-synuclein aggregation and ameliorates motor function deficits in rats: possible role of biochemical and inflammatory alterations. Behav Brain Res 296:177–190CrossRefPubMedGoogle Scholar
  57. Sharma N, Sharma S, Nehru B (2017) Curcumin protects dopaminergic neurons against inflammation-mediated damage and improves motor dysfunction induced by single intranigral lipopolysaccharide injection. Inflammopharmacology 25(3):351–368CrossRefPubMedGoogle Scholar
  58. Sikora E, Scapagnini G, Barbagallo M (2010) Curcumin, inflammation, ageing and age-related diseases. Immun Ageing 7:1CrossRefPubMedPubMedCentralGoogle Scholar
  59. Sofic et al (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56:978–982CrossRefPubMedGoogle Scholar
  60. Sulzer D et al (2000) Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci USA 97:11869–11874CrossRefPubMedPubMedCentralGoogle Scholar
  61. Uversky VN, Lee HJ, Li J, Fink AL, Lee SJ (2001) Stabilization of partially folded conformation during α-synuclein oligomerization in both purified and cytosolic preparations. J Biol Chem 276:43495–43498CrossRefPubMedGoogle Scholar
  62. Venkatesan P, Rao MN (2000) Structure-activity relationships for the inhibition of lipid peroxidation and the scavenging of free radicals by synthetic symmetrical curcumin analogues. J Pharm Pharmacol 52:1123–1128CrossRefPubMedGoogle Scholar
  63. Wang MS, Boddapati S, Emadi S, Sierks MR (2010) Curcumin reduces α-synuclein induced cytotoxicity in Parkinson’s disease cell model. BMC Neuroscience 11:57CrossRefPubMedPubMedCentralGoogle Scholar
  64. Winner B et al (2011) In vivo demonstration that α-synuclein oligomers are toxic. Proc Natl Acad Sci USA 108:4194–4199CrossRefPubMedPubMedCentralGoogle Scholar
  65. Wu DC et al (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci USA 100:6145–6150CrossRefPubMedPubMedCentralGoogle Scholar
  66. Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD (2002) Peroxynitrite mediates neurotoxicity of amyloid betapeptide1- 42- and lipopolysaccharide-activated microglia. J Neurosci 22(9):3484–3492PubMedGoogle Scholar
  67. Yang F et al (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901CrossRefPubMedGoogle Scholar
  68. Zahler WL, Cleland WW (1968) A specific and sensitive assay for disulphides. J Biol Chem 243(4):716–719PubMedGoogle Scholar
  69. Zhang W et al (2005) Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19(6):533–542CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of BiophysicsPanjab UniversityChandigarhIndia

Personalised recommendations