Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway

Cui,Qunli; Li,Xin; Zhu,Hongcan

doi:10.3892/mmr.2015.4657

Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway

Authors:
- Qunli Cui
- Xin Li
- Hongcan Zhu
View Affiliations

Affiliations: Department of Neurology, The Second Teaching Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China, Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: December 8, 2015 https://doi.org/10.3892/mmr.2015.4657
Pages: 1381-1388

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Parkinson's disease (PD) is an age‑related complex neurodegenerative disease that affects ≤80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT)‑injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase‑1 and NAD(P)H:quinone oxidoreductase 1, thus ameliorating ROT‑induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2‑related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT‑treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2‑specific short hairpin RNA, or the phosphoinositide 3‑kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT‑induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway.

View Figures

View References

1	Nutt JG and Wooten GF: Clinical practice. Diagnosis and initial management of Parkinson's disease. N Engl J Med. 353:1021–1027. 2005. View Article : Google Scholar : PubMed/NCBI
2	Camilleri A and Vassallo N: The centrality of mitochondria in the pathogenesis and treatment of parkinson's disease. CNS Neurosci Ther. 20:591–602. 2014. View Article : Google Scholar : PubMed/NCBI
3	Mariani E, Polidori MC, Cherubini A and Mecocci P: Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview. J Chromatogr B Analyt Technol Biomed Life Sci. 827:65–75. 2005. View Article : Google Scholar : PubMed/NCBI
4	Tolleson CM and Fang JY: Advances in the mechanisms of Parkinson's disease. Discov Med. 15:61–66. 2013.PubMed/NCBI
5	Sayre LM, Smith MA and Perry G: Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem. 8:721–738. 2001. View Article : Google Scholar : PubMed/NCBI
6	Perry TL and Yong VW: Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett. 67:269–274. 1986. View Article : Google Scholar : PubMed/NCBI
7	Bharath S, Hsu M, Kaur D, Rajagopalan S and Andersen JK: Glutathione, iron and Parkinson's disease. Biochem Pharmacol. 64:1037–1048. 2002. View Article : Google Scholar : PubMed/NCBI
8	Saravanan KS, Sindhu KM, Senthilkumar KS and Mohanakumar KP: L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats. Neurochem Int. 49:28–40. 2006. View Article : Google Scholar : PubMed/NCBI
9	Du XX, Xu HM, Jiang H, Song N, Wang J and Xie JX: Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson's disease. Neurosci Bull. 28:253–258. 2012. View Article : Google Scholar : PubMed/NCBI
10	Mythri RB and Bharath MM: Curcumin: A potential neuroprotective agent in Parkinson's disease. Curr Pharm Des. 18:91–99. 2012. View Article : Google Scholar : PubMed/NCBI
11	Dutta S, Padhye S, Priyadarsini KI and Newton C: Antioxidant and antiproliferative activity of curcumin semicarbazone. Bioorg Med Chem Lett. 15:2738–2744. 2005. View Article : Google Scholar : PubMed/NCBI
12	Biswas SK, McClure D, Jimenez LA, Megson IL and Rahman I: Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: Mechanism of free radical scavenging activity. Antioxid Redox Signal. 7:32–41. 2005. View Article : Google Scholar : PubMed/NCBI
13	Singh S and Khar A: Biological effects of curcumin and its role in cancer chemoprevention and therapy. Anticancer Agents Med Chem. 6:259–270. 2006. View Article : Google Scholar : PubMed/NCBI
14	Daniel S, Limson JL, Dairam A, Watkins GM and Daya S: Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain. J Inorg Biochem. 98:266–275. 2004. View Article : Google Scholar : PubMed/NCBI
15	Ataie A, Sabetkasaei M, Haghparast A, Moghaddam AH and Kazeminejad B: Neuroprotective effects of the polyphenolic antioxidant agent, Curcumin, against homocysteine-induced cognitive impairment and oxidative stress in the rat. Pharmacol Biochem Behav. 96:378–385. 2010. View Article : Google Scholar : PubMed/NCBI
16	Jagatha B, Mythri RB, Vali S and Bharath MM: Curcumin treatment alleviates the effects of glutathione depletion in vitro and in vivo: Therapeutic implications for Parkinson's disease explained via in silico studies. Free Radic Biol Med. 44:907–917. 2008. View Article : Google Scholar : PubMed/NCBI
17	Harish G, Venkateshappa C, Mythri RB, Dubey SK, Mishra K, Singh N, Vali S and Bharath MM: Bioconjugates of curcumin display improved protection against glutathione depletion mediated oxidative stress in a dopaminergic neuronal cell line: Implications for Parkinson's disease. Bioorg Med Chem. 18:2631–2638. 2010. View Article : Google Scholar : PubMed/NCBI
18	Chen J, Tang XQ, Zhi JL, Cui Y, Yu HM, Tang EH, Sun SN, Feng JQ and Chen PX: Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis. 11:943–953. 2006. View Article : Google Scholar : PubMed/NCBI
19	Cui QLSS: Curcumin antagonizes rotenone-induced injury of PC12 Cells by antioxidant activity. Acta Med Univ Sci Technol Huazhong. 39:37–46. 2010.
20	Tsou YH, Shih CT, Ching CH, Huang JY, Jen CJ, Yu L, Kuo YM, Wu FS and Chuang JI: Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity. Exp Neurol. 263:50–62. 2015. View Article : Google Scholar
21	Lee JM and Johnson JA: An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol. 37:139–143. 2004. View Article : Google Scholar : PubMed/NCBI
22	Kakkar V and Kaur IP: Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol. 49:2906–2913. 2011. View Article : Google Scholar : PubMed/NCBI
23	Mokrasch LC and Teschke EJ: Glutathione content of cultured cells and rodent brain regions: A specific fluorometric assay. Anal Biochem. 140:506–509. 1984. View Article : Google Scholar : PubMed/NCBI
24	Shinomol GK and Muralidhara: Prophylactic neuroprotective property of Centella asiatica against 3-nitropropionic acid induced oxidative stress and mitochondrial dysfunctions in brain regions of prepubertal mice. Neurotoxicology. 29:948–957. 2008. View Article : Google Scholar : PubMed/NCBI
25	Ohkawa H, Ohishi N and Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 95:351–358. 1979. View Article : Google Scholar : PubMed/NCBI
26	Lim JH, Kim KM, Kim SW, Hwang O and Choi HJ: Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: Novel cytoprotective mechanism against oxidative damage. Pharmacol Res. 57:325–331. 2008. View Article : Google Scholar : PubMed/NCBI
27	Lin TK, Cheng CH, Chen SD, Liou CW, Huang CR and Chuang YC: Mitochondrial dysfunction and oxidative stress promote apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade following chronic rotenone intoxication in rats. Int J Mol Sci. 13:8722–8739. 2012. View Article : Google Scholar : PubMed/NCBI
28	Coulom H and Birman S: Chronic exposure to rotenone models sporadic Parkinson's disease in Drosophila melanogaster. J Neurosci. 24:10993–10998. 2004. View Article : Google Scholar : PubMed/NCBI
29	Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV and Greenamyre JT: Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 3:1301–1306. 2000. View Article : Google Scholar : PubMed/NCBI
30	Madathil SK, Karuppagounder SS and Mohanakumar KP: Sodium salicylate protects against rotenone-induced parkinsonism in rats. Synapse. 67:502–514. 2013. View Article : Google Scholar : PubMed/NCBI
31	Santiago RM, Barbieiro J, Lima MM, Dombrowski PA, Andreatini R and Vital MA: Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine. Prog Neuropsychopharmacol Biol Psychiatry. 34:1104–1114. 2010. View Article : Google Scholar : PubMed/NCBI
32	Swarnkar S, Singh S, Mathur R, Patro IK and Nath C: A study to correlate rotenone induced biochemical changes and cerebral damage in brain areas with neuromuscular coordination in rats. Toxicology. 272:17–22. 2010. View Article : Google Scholar : PubMed/NCBI
33	Shinomol GK and Muralidhara: Bacopa monnieri modulates endogenous cytoplasmic and mitochondrial oxidative markers in prepubertal mice brain. Phytomedicine. 18:317–326. 2011. View Article : Google Scholar
34	Madathil KS, Karuppagounder SS, Haobam R, Varghese M, Rajamma U and Mohanakumar KP: Nitric oxide synthase inhibitors protect against rotenone-induced, oxidative stress mediated parkinsonism in rats. Neurochem Int. 62:674–683. 2013. View Article : Google Scholar : PubMed/NCBI
35	Liu CB, Wang R, Pan HB, Ding QF and Lu FB: Effect of lycopene on oxidative stress and behavioral deficits in rotenone induced model of Parkinson's disease. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 29:380–384. 2013.In Chinese. PubMed/NCBI
36	Zhang Q, Zhang J, Jiang C, Qin J, Ke K and Ding F: Involvement of ERK1/2 pathway in neuroprotective effects of pyrroloquinoline quinine against rotenone-induced SH-SY5Y cell injury. Neuroscience. 270:183–191. 2014. View Article : Google Scholar : PubMed/NCBI
37	Nguyen T, Sherratt PJ and Pickett CB: Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 43:233–260. 2003. View Article : Google Scholar
38	Wu J, Li Q, Wang X, Yu S, Li L, Wu X, Chen Y, Zhao J and Zhao Y: Neuroprotection by curcumin in ischemic brain injury involves the Akt/Nrf2 pathway. PLoS One. 8:e598432013. View Article : Google Scholar : PubMed/NCBI
39	Qin XY, Cheng Y and Yu LC: Potential protection of curcumin against intracellular amyloid beta-induced toxicity in cultured rat prefrontal cortical neurons. Neurosci Lett. 480:21–24. 2010. View Article : Google Scholar : PubMed/NCBI
40	Dickinson DA, Iles KE, Zhang H, Blank V and Forman HJ: Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J. 17:473–475. 2003.PubMed/NCBI
41	Gao S, Duan X, Wang X, Dong D, Liu D, Li X, Sun G and Li B: Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion. Food Chem Toxicol. 59:739–747. 2013. View Article : Google Scholar : PubMed/NCBI