Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

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.

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

  • 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 53:6819–6824

    Article  CAS  PubMed  Google Scholar 

  • Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398

    CAS  PubMed  Google Scholar 

  • Ahmad B, Lapidus LJ (2012) Curcumin prevents aggregation in α-synuclein by increasing reconfiguration rate. J Biol Chem 287:9193–9199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 37:813–822

    Article  CAS  PubMed  Google Scholar 

  • Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Rev Neurosci 5:S18–S25

    Article  Google Scholar 

  • 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 485–486

  • Behari M, Bhatnagar SP, Muthane U, Deo D (2002) Experiences of Parkinson’s disease in India. Lancet Neurol 1:258–262

    Article  PubMed  Google Scholar 

  • Betarbet R, Sherer TB, Di Monte DA, Greenamyre JT (2002) Mechanistic approaches to Parkinson’s disease pathogenesis. Brain Pathol 12(4):499–510

    Article  CAS  PubMed  Google Scholar 

  • Bharath et al (2002) Glutathione, iron and Parkinson’s disease. Biochem Pharmacol 64:1037–1048

    Article  CAS  PubMed  Google Scholar 

  • 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 107:7710–7715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown C, Neher JJ (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 41:242–247

    Article  CAS  PubMed  Google Scholar 

  • 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 585:1113–1120

    Article  CAS  PubMed  Google Scholar 

  • 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):133–136

    Article  PubMed  Google Scholar 

  • Cole GM, Teter B, Frautschy SA (2007) Neuroprotective effects of curcumin. Adv Exp Med Biol 595:197–212

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 4:1318–1320

    Article  CAS  PubMed  Google Scholar 

  • Cookson MR (2005) Biochemistry of Parkinson’s disease. Annu Rev Biochem 74:29–52

    Article  CAS  PubMed  Google Scholar 

  • 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 32:14465–14477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dutta G, Zhang P, Liu B (2008) The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol 22:453–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ehrnhoefer DE et al (2008) EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15:558–566

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL (1959) Tissue sulphydryl groups. Arch Biochem Biophy 82:70–77

    Article  CAS  Google Scholar 

  • Esposito E, Cuzzocrea S (2009) Role of nitroso radicals as drug targets in circulatory shock. Br J Pharmacol 157(4):494–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferreira N, Saraiva MJ, Almeida MR (2011) Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation. FEBS Lett 585:2424–2430

    Article  CAS  PubMed  Google Scholar 

  • Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 75:787–809

    Article  CAS  PubMed  Google Scholar 

  • 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 85:1694–1703

    Article  Google Scholar 

  • 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 104:1553–1564

    Article  CAS  PubMed  Google Scholar 

  • Hirsch EC, Vyas S, Hunot S (2012) Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord 18(1):S210–S212

    Article  PubMed  Google Scholar 

  • Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13(1):24–34

    PubMed  Google Scholar 

  • Jiao et al (2006) Iron chelation in the biological activity of curcumin. Free Radic Biol 40(7):1152–1160

    Article  CAS  Google Scholar 

  • Jiao et al (2009) Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 113(2):462–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jouihan H (2012) Iron—Prussian blue reaction—Mallory’s method. Bio-protocol 2(13):e222. doi:10.21769/BioProtoc.222

    Google Scholar 

  • 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):15240–15247

    Article  CAS  PubMed  Google Scholar 

  • Karpinar DP et al (2009) Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson’s disease models. EMBO J 28:3256–3268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 73:51–59

    Article  CAS  Google Scholar 

  • 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):2983–2994

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):8370–8377

    CAS  PubMed  Google Scholar 

  • 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 63:439–444

    Article  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    CAS  PubMed  Google Scholar 

  • MacMillan-Crow LA, Crow JP, Thompson JA (1998) Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry 37:1613–1622

    Article  CAS  PubMed  Google Scholar 

  • 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 12:1107–1123

    Article  CAS  PubMed  Google Scholar 

  • Martin HL, Teismann P (2009) Glutathione—a review on its role and significance in Parkinson’s disease. FASEB J. 23(10):3263–3272

    Article  CAS  PubMed  Google Scholar 

  • 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 120:440–452

    Article  CAS  PubMed  Google Scholar 

  • 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 583:787–791

    Article  CAS  PubMed  Google Scholar 

  • Olanow W (1992) An introduction to the free-radical hypothesis in Parkinsons-disease. Ann Neurol 32:S2–S9

    Article  CAS  PubMed  Google Scholar 

  • Ono K, Yamada M (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro. J Neurochem 97:105–115

    Article  CAS  PubMed  Google Scholar 

  • Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE (2008) Curcumin inhibits aggregation of α-synuclein. Acta Neuropathol 115:479–489

    Article  CAS  PubMed  Google Scholar 

  • Paxinos GW, Watson C (2005) The rat brain in stereotaxic coordinates. Academic Press, Oxford

    Google Scholar 

  • Pearse AGE (1968) Histochemical, theoretical and applied, 3rd edn. Churchill Livingstone, London, p 660

    Google Scholar 

  • 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):399–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 199:249–256

    Article  CAS  PubMed  Google Scholar 

  • 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 153:443–455

    Article  CAS  PubMed  Google Scholar 

  • 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 18:912–914

    Article  PubMed  Google Scholar 

  • Rappold PM, Tieu K (2010) Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics 7(4):413–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riederer P, Sofic P, Rrausch WD, Schmidt B, Reynolds GP (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52:515–520

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Sharma N, Nehru B (2015) Characterization of the lipopolysaccharide induced model of Parkinson’s disease: role of oxidative stress and neuroinflammation. Neurochem Int 87:92–105

    Article  CAS  PubMed  Google Scholar 

  • 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 296:177–190

    Article  CAS  PubMed  Google Scholar 

  • 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):351–368

    Article  CAS  PubMed  Google Scholar 

  • Sikora E, Scapagnini G, Barbagallo M (2010) Curcumin, inflammation, ageing and age-related diseases. Immun Ageing 7:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sofic et al (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56:978–982

    Article  CAS  PubMed  Google Scholar 

  • Sulzer D et al (2000) Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci USA 97:11869–11874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 276:43495–43498

    Article  CAS  PubMed  Google Scholar 

  • 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 52:1123–1128

    Article  CAS  PubMed  Google Scholar 

  • Wang MS, Boddapati S, Emadi S, Sierks MR (2010) Curcumin reduces α-synuclein induced cytotoxicity in Parkinson’s disease cell model. BMC Neuroscience 11:57

    Article  PubMed  PubMed Central  Google Scholar 

  • Winner B et al (2011) In vivo demonstration that α-synuclein oligomers are toxic. Proc Natl Acad Sci USA 108:4194–4199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 100:6145–6150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):3484–3492

    CAS  PubMed  Google Scholar 

  • Yang F et al (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901

    Article  CAS  PubMed  Google Scholar 

  • Zahler WL, Cleland WW (1968) A specific and sensitive assay for disulphides. J Biol Chem 243(4):716–719

    CAS  PubMed  Google Scholar 

  • Zhang W et al (2005) Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19(6):533–542

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

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

Author information

Authors and Affiliations

  1. Department of Biophysics, Panjab University, Chandigarh, 160014, India

    Neha Sharma & Bimla Nehru

Authors
  1. Neha Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bimla Nehru
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bimla Nehru.

Ethics declarations

Conflict of interest

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, N., Nehru, B. Curcumin affords neuroprotection and inhibits α-synuclein aggregation in lipopolysaccharide-induced Parkinson’s disease model. Inflammopharmacol 26, 349–360 (2018). https://doi.org/10.1007/s10787-017-0402-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-017-0402-8

Keywords

Search

Navigation