Potential therapeutic effects of antagonizing adenosine A2A receptor, curcumin and niacin in rotenone-induced Parkinson’s disease mice model


Parkinson’s disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson’s disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals’ behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson’s disease eradication.

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  1. 1.

    Rajabally YA, Martey J (2011) Neuropathy in Parkinson disease: prevalence and determinants. Neurology 77:1947–1950

  2. 2.

    Taylor TN, Greene JG, Miller GW (2010) Behavioral phenotyping of mouse models of Parkinson’s disease. Behav Brain Res 211:1–10

  3. 3.

    Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bio Essays 24:308–318

  4. 4.

    Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JTM (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 34:279–290

  5. 5.

    Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62:132–144

  6. 6.

    Bordone MP, Salman MM, Titus HE, Amini E, Andersen JV, Chakraborti B et al (2019) The energetic brain—a review from students to students. J Neurochem 151:139–165

  7. 7.

    Crispo JAG, Fortin Y, Thibault DP, Emons M, Bjerre LM, Kohen DE, Perez-Lloret S, Mattison D, Willis AW, Krewski D (2015) Trends in inpatient antiparkinson drug use in the USA, 2001–2012. Eur J Clin Pharmacol 71:1011–1019

  8. 8.

    Perez-Pardo P, Broersen LM, Kliest T, van Wijk N, Attali A, Garssen J, Kraneveld AD (2018) Additive effects of levodopa and a neurorestorative diet in a mouse model of Parkinson’s disease. Front Aging Neurosci 10:237

  9. 9.

    Jacob A, Wu R, Zhou M, Wang P (2007) Mechanism of the anti-inflammatory effect of curcumin: PPAR-gamma activation. PPAR Res 2007:89369

  10. 10.

    Zhao LN, Chiu SW, Benoit J, Chew LY, Mu Y (2012) The effect of curcumin on the stability of aβ dimers. J Phys Chem B 116:7428–7435

  11. 11.

    Trujillo J, Chirino YI, Molina-Jijón E, Andérica-Romero AC, Tapia E, Pedraza-Chaverrí J (2013) Reno-protective effect of the antioxidant curcumin: recent findings. Redox Biol 1:448–456

  12. 12.

    Reeta KH, Mehla J, Gupta YK (2010) Curcumin ameliorates cognitive dysfunction and oxidative damage in phenobarbitone and carbamazepine administered rats. Eur J Pharmacol 644:106–112

  13. 13.

    Tsai YM, Chien CF, Lin LC, Tsai TH (2011) Curcumin and its nano-formulation: the kinetics of tissue distribution and blood-brain barrier penetration. Int J Pharm 416:331–338

  14. 14.

    Garg A, Sharma A, Krishnamoorthy P, Garg J, Virmani D, Sharma T, Stefanini G, Kostis JB, Mukherjee D, Sikorskaya E (2017) Role of niacin in current clinical practice: a systematic review. Am J Med 130:173–187

  15. 15.

    Feingold KR, Moser A, Shigenaga JK, Grunfeld C (2014) Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages. J Lipid Res 55:2501–2508

  16. 16.

    Chapman MJ (2004) Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 20:1253–1268

  17. 17.

    Motawi TK, Darwish HA, Hamed MA, El-Rigal NS, Aboul Naser AF (2017) A therapeutic insight of niacin and coenzyme Q10 against diabetic encephalopathy in rats. Mol Neurobiol 54:1601–1611

  18. 18.

    Wakade C, Chong R (2014) A novel treatment target for Parkinson’s disease. J Neurol Sci 347:34–38

  19. 19.

    Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Muller-Fielitz H, Pokorna B, Vollbrandt T, Stolting I, Nadrowitz R, Okun JG, Offermanns S, Schwaninger M (2014) The betahydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun 5:3944

  20. 20.

    Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, Shehadah A, Roberts C, Liu X, Lu M, Chen J (2011) Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. Exp Neurol 232:299–308

  21. 21.

    Fathalla AM, Soliman AM, Ali MH, Moustafa AA (2016) Adenosine A2A receptor blockade prevents rotenone-induced motor impairment in a rat model of Parkinsonism. Front Behav Neurosci 2016(10):1–5

  22. 22.

    El Shebiney SA, El-Denshary ES, Abdel-Salam OME, Salem NA, El-Khyat ZA, El Shaffie N, Abdallah DM (2014) Cannabis resin extract in Parkinson’s disease: behavioral, neurochemical, and histological evaluation. Cell Biol Res Ther 3:1

  23. 23.

    Rajeswari A, Sabesan M (2008) Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice. Inflammopharmacology 16:96–99

  24. 24.

    Yan T, Chopp M, Ye X, Liu Z, Zacharek A, Cui Y, Roberts C, Buller B, Chen J (2012) Niaspan increases axonal remodeling after stroke in type 1 diabetic rats. Neurobiol Dis 46:157–164

  25. 25.

    Alam M, Schmidt WJ (2004) L-DOPA reverses the hypokinetic behaviour and rigidity in rotenone-treated rats. Behav Brain Res 153:439–446

  26. 26.

    Sanberg P, Martinez R, Shytle R, Cahill D (1996) The catalepsy test: is a standardized method possible? In: Sanberg PR, Ossenkopp KP, Kavaliers M (eds) Motor activity and movement disorders. Humana Press, New York

  27. 27.

    Khalil WKB, Booles HF (2011) Protective role of selenium against over-expression of cancer-related apoptotic genes induced by o-Cresol in rats. Arh Hig Rad Toksikol 62:121–129

  28. 28.

    Linjawi SAA, Khalil WKB, Salem LM (2014) Detoxified Jatropha curcaskernel meal impact against benzene-induced genetic toxicity in male rats. Int J Pharm 4:57–66

  29. 29.

    Cerri S, Ghezzi C, Sampieri M, Siani F, Avenali M, Dornini G, Zangaglia R, Minafra B, Blandini F (2018) The exosomal/total α synuclein satio in plasma is associated with glucocerebrosidase activity and correlates with measures of disease severity in PD patients. Front Cell Neurosci 12:125

  30. 30.

    Wen G, Hui W, Dan C, Xiao-Qiong W, Jian-Bin T, Chang-Qi L (2009) The effects of exercise-induced fatigue on acetylcholinesterase expression and activity at rat neuromuscular junctions. Acta Histochem Cytochem 42:137–142

  31. 31.

    Zagrodzka J, Romaniuk A, Wieczorek M, Boguszewski P (2000) Bicuculline administration into ventromedial hypothalamus: effects on fear and regional brain monoamines and GABA concentrations in rats. Acta Neurobiol Exp 60:333–343

  32. 32.

    Moron MS, Depierre JW, Mannervik B (1979) Level of glutathione, glutathione reductase and glutathone-S-transferase activities in rat lung and liver. Biochem Biophys Act 582:67–78

  33. 33.

    Wills ED (1966) Mechanism of lipid peroxide formation in animal tissue. Biochem J 99:667–676

  34. 34.

    Kono Y (1978) Generation of superoxide radical during auto-oxidation of hydroxylamine and an assay of superoxide dismutase. Arch Biochem Biophys 186:189–195

  35. 35.

    Rice ME, Shelton E (1957) Comparison of the reduction of two tetrazolium salts with succinoxidase activity of tissue homogenates. J Nat Cancer Inst 18:117–125

  36. 36.

    Babson AL, Babson SR (1973) Kinetic colorimetric measurement of serum lactate dehydrogenase activity. Clin Chem 19:766–769

  37. 37.

    Sun H, Li P, Chen W, Xiong X, Han Y (2012) Angiotensin II and angiotensin-(1-7) in paraventricular nucleus modulate cardiac sympathetic afferent reflex in renovascular hypertensive rats. PLoS ONE 7:1–11

  38. 38.

    Sun X, Wang D, Yu H, Hu L (2010) Serial cytokine levels during wound healing in rabbit maxillary sinus mucosa. Acta Otorrinolaringol 130:607–613

  39. 39.

    Schreiber G, Tsykin A, Aldred AR, Thomas T, Fung WP, Dickson PW, Cole T, Birch H, De Jong FA, Milland J (1989) The acute phase response in the rodent. Ann N Y Acad Sci 557:61–85

  40. 40.

    Pradeep AR, Suke DK, Prasad MV, Singh SP, Martande SS, Nagpal K, Naik SB, Guruprasad CN, Raju AP, Singh P, Siddaya M (2016) Expression of key executioner of apoptosis caspase-3 in periodontal health and disease. J Invest Clin Dent 7:174–197

  41. 41.

    Lu T, Xu Y, Mericle MT, Mellgren RL (2002) Participation of the conventional calpains in apoptosis. Biochem Biophys Acta 1590:16–26

  42. 42.

    Bancroft J, Stevens A (1996) Theory and practice of histological techniques, 4th edn. Churchill Livingstone, London, pp 40–138

  43. 43.

    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164

  44. 44.

    Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8:1150–1157

  45. 45.

    Ulusoy A, Rusconi R, Perez-Revuelta BI, Musgrove RE, Helwig M, Winzen-Reichert B, Di Monte DA (2013) Caudo-rostral brain spreading of alpha-synuclein through vagal connections. EMBO Mol Med 5:1051–1059

  46. 46.

    El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, Allsop D (2006) Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J 20:419–425

  47. 47.

    Grondin R, Bedard PJ, HadjTahar A, Gregoire L, Mori A, Kase H (1999) Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology 52:1673–1677

  48. 48.

    Ferre S, Popoli P, Gimenez-Llort L, Rimondini R, Muller CE, Stromberg I, Ögren SO, Fuxe K (2001) Adenosine/dopamine interaction: implications for the treatment of Parkinson’s disease. Parkinsonism Relat Disord 7:235–241

  49. 49.

    Ascherio A, Zhang SM, Hernan MA, Kawachi I, Colditz GA, Speizer FE, Willett WC (2001) Prospective study of coffee consumption and risk of Parkinson’s disease in men and women. Ann Neurol 50:56–63

  50. 50.

    Calon F, Dridi M, Hornykiewicz O, BeÂdard PJ, Rajput AH, Di Paolo T (2004) Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain 127:1075–1084

  51. 51.

    Kachroo A, Schwarzschild MA (2012) Adenosine A2A receptor gene disruption protects in an α-synuclein model of Parkinson’s disease. Ann Neurol 2(71):278–282

  52. 52.

    Dungo R, Deeks ED (2013) Istradefylline: first global approval. Drugs 73:875–882

  53. 53.

    Lu J, Cui J, Li X, Wang X, Zhou Y, Yang W, Chen M, Zhao J, Gang Pe (2016) An anti-Parkinson’s disease drug via targeting adenosine A2A receptor enhances amyloid-β generation and γ-secretase activity. PLoS ONE 11:e0166415

  54. 54.

    Compta Y, Parkkinen L, Kempster P, Selikhova M, Lashley T, Holton JL, Lees AJ, Revesz T (2014) The significance of α-synuclein, amyloid-β and tau pathologies in Parkinson’s disease progression and related dementia. Neurodegener Dis 13:154–156

  55. 55.

    Shen J (2010) Impaired neurotransmitter release in Alzheimer’s and Parkinson’s diseases. Neurodegener Dis 7:80–83

  56. 56.

    Perez-Lloret S, Barrantes FJ (2016) Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. NPJ Parkinson’s Dis 2:16001

  57. 57.

    Muthian G, Mackey V, Prasad K, Charlton C (2018) Curcumin and an antioxidant formulation protect C57BL/6 J mice from MPTP-induced Parkinson’s disease like changes: potential neuroprotection for neurodegeneration. J. Parkinsonism Restless Legs Synd 8:49–59

  58. 58.

    Martin LJ (2008) DNA damage and repair: relevance to mechanisms of neurodegeneration. Neuropathol Exp Neurol 67:377–387

  59. 59.

    Zawada WM, Mrak RE, Biedermann JA, Palmer QD, Gentleman SM, Aboud O, Griffin WST (2015) Loss of angiotensin II receptor expression in dopamine neurons in Parkinson’s disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation. Acta Neuropathol Commun 3:9

  60. 60.

    Saeed A, Shakir L, Khan MA, Ali A, Yousaf M, Zaidi AA (2017) Haloperidol induced Parkinson’s disease mice model and motor-function modulation with Pyridine-3-carboxylic acid. Biomed Res Ther 4:1305–1317

  61. 61.

    Farshbaf MJ (2017) Succinate dehydrogenase in Parkinson’s disease. Front Biol 12:175–182

  62. 62.

    Ludtmann MHR, Angelova PR, Horrocks MH, Choi ML, Rodrigues M, Baev AY, Berezhnov AV, Yao Z, Little D, Banushi B, Al-Menhali AS, Ranasinghe RT, Whiten DR, Yapom R, Dolt KS, Devine MJ, Gissen P, Kunath T, Jaganjac M, Pavlov EV, Klenerman D, Abramov AY, Gandhi S (2018) α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nat Commun 12:2293

  63. 63.

    Ross JM, Öberg J, Brené S, Coppotelli G, Terzioglu M, Pernold K, Goinyg M, Sitnikov R, Kehr J, Trifunovic A, Larsson N, Hoffer BJ, Olson L (2010) High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. PNAS 107:20087–20092

  64. 64.

    Zhou J, Liu T, Guo H, Cui H, Li P, Feng D, Hu E, Huang Q, Yang A, Zhou J, Luo J, Tang T, Wang Y (2018) Lactate potentiates angiogenesis and neurogenesis in experimental intracerebral hemorrhage. Exp Mol Med 50:78

  65. 65.

    Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, Greenamyre JT, Liu RM, Forman HJ, Andersen JK (2000) Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex 1 activity: implications for Parkinson’s disease. J Biol Chem 2000(275):260996

  66. 66.

    Jiang T, Gao L, Lu J, Zhang YD (2013) ACE2-Ang-(1–7)-mas axis in brain: a potential target for prevention and treatment of ischemic stroke. Curr Neuropharmacol 11:209–217

  67. 67.

    Garrido-Gil P, Valenzuela R, Villar-Cheda B, Lanciego JL, Labandeira-Garcia JL (2013) Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin-angiotensin system in the nigra. Brain Struct Funct 218:373–388

  68. 68.

    Benigni A, Cassis P, Remuzzi G (2010) Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2:247–257

  69. 69.

    Sawada H, Oeda T, Umemura A, Tomita S, Kohsaka M, Park K, Yamamoto K, Sugiyama H (2015) Baseline C-reactive protein levels and life prognosis in Parkinson disease. PLoS ONE 10:e0134118

  70. 70.

    Qiu X, Xiao Y, Wu J, Gan L, Huang Y, Wang J (2019) C-reactive protein and risk of Parkinson’s disease: A systematic review and meta-analysis. Neurology, Front.

  71. 71.

    Khadrawy YA, Salem AM, El-Shamy KA, Ahmed EK, Fadl NN, Hosny EN (2017) Neuroprotective and therapeutic effect of caffeine on the rat model of Parkinson’s disease induced by rotenone. J Diet Suppl 14:553–572

  72. 72.

    Hegde ML, Hegde PM, Holthauzen LM, Hazra TK, Rao KS, Mitra S (2010) Specific inhibition of NEIL-initiated repair of oxidized base damage in human genome by copper and iron: potential etiological linkage to neurodegenerative diseases. J Biol Chem 285:28812–28825

  73. 73.

    Wang XS, Zhang ZR, Zhang MM, Sun MX, Wang WW, Xie CL (2017) Neuroprotective properties of curcumin intoxin-base animal models of Parkinson’s disease: a systematic experiment literatures review. BMC Comp Alt Med 17:412

  74. 74.

    Picada JN, Floresa DG, Zettler CG, Marroni NP, Roesler R, Henriques JA (2003) D NA damage in brain cells of mice treated with an oxidized form of apomorphine. Mol Brain Res 114:80–85

  75. 75.

    Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 70:373–381

  76. 76.

    Hirsch EC, Hunot S, Hartmann A (2005) Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord 11:S9–S15

  77. 77.

    Yang R, Dunn JF (2019) Multiple sclerosis disease progression: contributions from a hypoxia-inflammation cycle. Mult Scler 25:1715–1718

  78. 78.

    Hofmann KW, Schuh AFS, Saute J, Townsend R, Fricke D, Leke R, Souza DO, Portela LV, Chaves MLF, Rieder CRM (2009) Interleukin-6 serum levels in patients with Parkinson’s disease. Neurochem Res 34:1401–1404

  79. 79.

    Bessler H, Djaldetti R, Salman H, Bergman M, Djaldetti M (1999) IL-1b, IL-2, IL-6 and TNF-a production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomed Pharmacother 53:141–145

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TKM, NAHS and MAH: Participated in study design, revised the statistical analysis and revised the manuscript. SAA: Analyzed the histopathological pictures, drafted and revised this section. WKBH: Conducted the genetic and DNA analysis, drafted and revised this section. YRA: Conducted the biochemical parameters, analyzed the data and drafted the article. All authors revised the final form of the paper and agreed for publication.

Correspondence to Manal A. Hamed.

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Animals care during the experiments were carried out in keeping with agreement of the Medical Ethical Committee, National Research Centre, Egypt (Approval No. 16089) and Ethics Committee of Faculty of Pharmacy, Cairo University, Cairo, Egypt (BC 1839). Basic housing requirements and regular inspection of facilities that mandate the control of pain and suffering during the experiment were conducted. Euthanasia was done rapidly and painlessly to be sure that the animals do not suffer at any stage of the experiment. Getting-rid of the animals after termination was done rapidly by the aid of the Safety and Health Committee at National Research Centre, Dokki, Giza, Egypt.

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Motawi, T.K., Sadik, N.A.H., Hamed, M.A. et al. Potential therapeutic effects of antagonizing adenosine A2A receptor, curcumin and niacin in rotenone-induced Parkinson’s disease mice model. Mol Cell Biochem 465, 89–102 (2020) doi:10.1007/s11010-019-03670-0

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  • Curcumin
  • Niacin
  • Rotenone
  • Parkinson’s disease
  • ZM241385