Curcumin modulation of L-dopa and rasagiline-induced neuroprotection in rotenone model of Parkinson’s disease

Document Type : Original Article


1 Department of Narcotics, Ergogenics, and Poisons, Medical Research Division, National Research Centre, Cairo, Egypt

2 Department of Pathology, Medical Research Division, National Research Centre, Cairo, Egypt

3 Department of Research on Children with Special Needs, Medical Research Division, National Research Centre, Cairo, Egypt


Objective(s): Parkinson’s disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic antioxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced  PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied.
Materials and Methods: Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included.
Results: Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline.
Conclusion: These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice. 


1. Rossi A, Berger K, Chen H, Leslie D, Mailman RB, Huang X. Projection of the prevalence of Parkinson’s disease in coming decades: revisited. Mov Disord 2018; 33: 156–159.
2. Jellinger KA. Recent developments in the pathology of Parkinson’s disease. J Neural Transm Suppl 2002; 62:347–376.
3. Santens P, Boon P, Van Roost D, Caemaert J. The pathophysiology of motor symptoms in Parkinson’s disease. Acta Neurol Belg 2003; 103:129–134.
4. Manisha G, Meenakshi C, Wamik A. Therapeuic role of L-DOPA produced as a secondary metabolite from different legumes and plant sources. AP 2012; 1: 1-8.
5. Sahin G,  Kirik D. Efficacy of L-DOPA therapy in Parkinson’s disease. In: Amino Acids in Human Nutrition and Health (ed JPF D’Mello) 2011, CAB International.: 454-463.
6. Nayak L and Henchcliffe C. Rasagline in treatment of Parkinson Parkinson’s disease. Neuropsychiatr Dis Treat 2008; 4: 23–32.
7. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as ‘‘Curecumin’’: From kitchen to clinic. Biochem Pharmacol 2008; 75: 787-809
8. Darvesh AS, Carroll RT, Bishayee A, Novotny NA, Geldenhuys WJ, Van der Schyf CJ. Curcumin and neurodegenerative diseases: A perspective. Expert Opin Investig Drugs 2012; 21: 1123-1140. 
9.  Giri RK, Rajagopal V, Kalra VK. Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor. J Neurochem 2004;  91:1199–1210.
10. El-Shamarka  MEA, Eliwa HA, Ahmed MAE. Inhibition of boldenone induced aggression in rats by curcumin: Targeting TLR4/MyD88/TRAF‐6/NF‐κB pathway. J Biochem Mol Toxicol 2022;36:e22936.
11. Tieu, K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb Perspect Med 2011; 1: a009316.
12. Alam M, Schmidt WJ. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 2002; 136: 317–324.
13. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000; 3:1301–1306.
14. Uversky V.N. Neurotoxicant induced animal models of Parkinson’s disease: understanding the role of rotenone,maneb and paraquatinneurodegeneration. Cell Tissue Res 2004; 318: 225–241.
15. Ruiz-Larrea MB, Leal AM, Liza M, Lacort M, de Groot H. Anti-oxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 1994; 59:383-388.
16. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82:70-77. 
17. Moshage H, Kok B, Huizenga JR. Nitrite and nitrate determination in plasma: A critical evaluation. Clin Chem 1995; 41:892–896.
18. Schaar KL, Brenneman MM, Savitz SI. Functional assessments in the rodent stroke model. Exp Transl Stroke Med 2010; 2:13.
19. Crawley JN. What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. 2nd ed. Hoboken: Wiley; 2017.
20. Rogers DC, Campbell CA, Stretton JL, Mackay KB.  Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke 1997; 28, 2060–2065.
21. Baird AL, Meldrum A, Dunnett SB. The staircase test of skilled reaching in mice. Brain Res Bull 2001; 54:243–250.
22. Chen J, Jin K, Chen M, Pei W, Kawaguchi K, Greenberg DA. Early detection of DNA strand breaks in the brain after transient focal ischemia: Implications for the role of DNA damage in apoptosis and neuronal cell death. J Neurochem 1997; 69: 232-245.
23. Wang JH, Gouda-Vossos A, Dzamko N, Halliday G, Huang Y. DNA extraction from fresh-frozen and formalin-fixed, paraffin embedded human brain tissue. Neurosci Bull 2013; 29: 649-654.
24. Sherer TB, Kim JH, Betarbet R, Greenamyre JT. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 2003;179:9-16.
25. Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT. A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 2009; 34:279–290.
26. Abdel-Salam OME, El-Shamarka M E-S, Omara EA. Grape seed extract exerts an anti-apoptotic effect and attenuates the decrease in striatal tyrosine hydroxylase in rotenone-treated mice. Reactive Oxygen Species 2019; 7:30-46. 
27. Abdel-Salam, OME, Omara, EA, El-Shamarka, ME-S, Hussein, JS. Nigrostriatal damage after systemic rotenone and/or lipopolysaccharide and the effect of cannabis. Comp Clin Pathol 2014; 23: 1343–1358.  
28. Hayyan M, Hashim MA, AlNashef IM. Superoxide ion: Generation and chemical implications. Chem Rev 2016; 116: 3029–3085.
29. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 2003; 278:8516-8525.
30. Chang CY, Song MJ, Yoon HJ, Jeon SB, Suk K, Kim IH, et al. Myeloperoxidase acts as a double-edged sword in rotenone-exposed brain-resident immune cells. J Immunol 2011;186:116-132.
31. Lee DH, Gold R, Linker RA. Mechanismsof oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci 2012; 13, 11783-11803.
32. Yan  MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 2012; 62: 90-101.
33. Abdel-Salam OME, Sleem AA, Youness ER, Mohammed NA, Omara EA, Shabana ME. Neuroprotective effects of the glutathione precursor N-acetylcysteine against rotenone- induced neurodegeneration. Reactive Oxygen Species 2019; 8:231-244.
34. Bashkatova V, Alam M, Vanin A, Schmidt WJ. Chronic administration of rotenone increases levels of nitric oxide and lipid peroxidation products in rat brain. Exp Neurol 2004;186:235-241.
35. Abdel-Salam OE, Omara EA, Youness ER, Khadrawy YA, Mohammed NA, Sleem AA. Rotenone-induced nigrostriatal toxicity is reduced by methylene blue. J Neurorestoratol 2014; 2:65-80.
36. Forstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J 2012; 33: 829-837.
37. Brown GC. Nitric oxide and neuronal death. Nitric Oxide 2010; 23:153-165.
38. Xiong ZK, Lang J, Xu G, Li HY, Zhang Y, Wang L, et al. Excessive levels of nitric oxide in rat model of Parkinson’s disease induced by rotenone. Exp Ther Med 2015; 9: 553-558. 
39. Gao B, Chang C, Zhou J, Zhao T, Wang C, Li C, et al. Pycnogenol protects against rotenone-induced neurotoxicity in PC12 cells through regulating NF-κB-iNOS signaling pathway. DNA Cell Biol 2015; 34: 643-649.
40. Henderson ND,Turri MG, DeFries JC, Flint J. QTL analysis of multiple behavioral measures of anxiety in mice. Behav Genet 2004; 34:267-293. 
41. Lever C, Burton S, O’Keefe J. Rearing on hind legs, environmental novelty, and the hippocampal formation. Rev Neurosci 2006; 17:111-133. 
42. Swanson CJ, Heath S, Stratford TR, Kelley AE. Differential behavioral responses to dopaminergic stimulation of nucleus accumbens subregions in the rat. Pharmacol Biochem Behav 1997;58:933-945.
43. El- Shamarka MEA, Kozman MR, Messiha BAS. The protective effect of inosine against rotenone-induced Parkinson’s disease in mice; role of oxido-nitrosative stress, ERK phosphorylation, and A2AR expression. Naunyn Schmiedeberg’s Arch Pharmacol 2020; 393:1041-1053.
44. Aggarwal BB, Sundaram, C, Malani N, Ichikawa H. Curcumin: The Indian solid gold (molecular targets and therapeutic uses of curcumin in health and disease). Adv Exp Med Biol 2007; 595: 1-75. 
45. Aly MAS, El-Shamarka MEA, Soliman TN, Elgabry MAE. Protective effect of nanoencapsulated curcumin against boldenone-induced testicular toxicity and oxidative stress in male albino rats. Egyptian Pharm J 2021; 20: 72-81.
46. Zhao BL, Li XJ, He RG, Cheng SJ, Xin WJ. Scavenging effect of extracts of green tea and natural anti-oxidants on active oxygen radicals. Cell Biophys 1989; 14: 175-185.
47. Sreejayan S, Rao MN. Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol 1997; 49: 105-107.
48. Liu Z, Yu Y, Lee X, Ross CA. Curcumin protects against A53T alpha-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol Res 2011; 63: 439–444.
49. Huang HC, Chang P,  Dai XL, Jiang ZF. Protective effects of curcumin on amyloid-b-induced neuronal oxidative damage. Neurochem Res 2012; 37:1584–1597. 
50. Du XX, Xu HM, Jiang H, Song N, Wang J, Xie JX. Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson’s disease. Neurosci Bull 2012; 28: 253–258.
51. Good PF, Olanow CW, Perl DP. Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study. Brain Res 1992; 593: 343-346.
52. Floyd RA. Anti-oxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999; 222:236‒245.
53. Schapira AHV. The use of rasagiline in Parkinson’s disease. J Neural Transm 2006; 71: 157–161.
54. Mandel S, Weinreb O, Amit T, Youdim MBH. Mechanism of neuroprotection of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Rev 2005; 48: 379–387
55. Maruyama W, Nitta A, Shamoto-Nagai M. N-propargyl-1(R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-k B transcription factor. Neurochem Intl 2004; 44: 393–400.
56. Araque A, Navarrete M. Glial cells in neuronal network function. Philos Trans R Soc Lond B Biol Sci 2010; 365:2375‒2381.
57. O’Callaghan JP, Sriram K. Glial fibrillary acidic protein and related glial proteins as biomarkers of neurotoxicity. Expert Opin Drug Saf 2005; 4:433‒442. 
58. Swarnkar S, Goswami P,  Kumar Kamat P, Gupta S, Patro IK, Singh S. Rotenone-induced apoptosis and role of calcium: A study on Neuro-2a cells. Arch Toxicol 2012; 86:1387–1397.
59. Jia H, Liu Z, Li X, Feng Z, Hao J, Li  X, et al. Synergistic anti-Parkinsonism activity of high doses of B vitamins in a chronic cellular model. Neurobiol Aging 2010; 31:636-646.