Top

Published in:

01-04-2018 | Original Article

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

Authors: Neha Sharma, Bimla Nehru

Published in: Inflammopharmacology | Issue 2/2018

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.

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 53:6819–6824CrossRefPubMed

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

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

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 37:813–822CrossRefPubMed

Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Rev Neurosci 5:S18–S25CrossRef

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 1:258–262CrossRefPubMed

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

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

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 107:7710–7715CrossRefPubMedPubMedCentral

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

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 585:1113–1120CrossRefPubMed

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):133–136CrossRefPubMed

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

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 4:1318–1320CrossRefPubMed

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

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 32:14465–14477CrossRefPubMedPubMedCentral

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

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

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

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

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

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

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 85:1694–1703CrossRef

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 104:1553–1564CrossRefPubMed

Hirsch EC, Vyas S, Hunot S (2012) Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord 18(1):S210–S212CrossRefPubMed

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

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

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

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

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):15240–15247CrossRefPubMed

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

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 73:51–59CrossRef

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):2983–2994CrossRefPubMedPubMedCentral

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):8370–8377PubMed

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 63:439–444CrossRefPubMed

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

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

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 12:1107–1123CrossRefPubMed

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

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 120:440–452CrossRefPubMed

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 583:787–791CrossRefPubMed

Olanow W (1992) An introduction to the free-radical hypothesis in Parkinsons-disease. Ann Neurol 32:S2–S9CrossRefPubMed

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

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

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

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

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):399–409CrossRefPubMedPubMedCentral

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 199:249–256CrossRefPubMed

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 153:443–455CrossRefPubMed

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 18:912–914CrossRefPubMed

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

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

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

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

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 296:177–190CrossRefPubMed

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):351–368CrossRefPubMed

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

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

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

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 276:43495–43498CrossRefPubMed

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 52:1123–1128CrossRefPubMed

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

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

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 100:6145–6150CrossRefPubMedPubMedCentral

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):3484–3492PubMed

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

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

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

Title: Curcumin affords neuroprotection and inhibits α-synuclein aggregation in lipopolysaccharide-induced Parkinson’s disease model
Authors: Neha Sharma
Bimla Nehru
Publication date: 01-04-2018
Publisher: Springer International Publishing
Published in: Inflammopharmacology / Issue 2/2018
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-017-0402-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

Diethylcarbamazine attenuates the expression of pro-fibrogenic markers and hepatic stellate cells activation in carbon tetrachloride-induced liver fibrosis

Molecular signature of nitric oxide on major cancer hallmarks of colorectal carcinoma

Constituents of leaves from Bauhinia curvula Benth. exert gastroprotective activity in rodents: role of quercitrin and kaempferol

The impact of mangiferin from Belamcanda chinensis on experimental colitis in rats

Inhibition of proinflammatory pathways by bioactive fraction of Tinospora cordifolia

PPARα/γ antagonists reverse the ameliorative effects of osthole on hepatic lipid metabolism and inflammatory response in steatohepatitic rats