Open Access

Sulforaphane prevents PC12 cells from oxidative damage via the Nrf2 pathway

  • Authors:
    • Bing Bao
    • Man‑Qing Zhang
    • Zhi‑Ying Chen
    • Xiang‑Bing Wu
    • Zhong‑Bing Xia
    • Jing‑Yan Chai
    • Xiao‑Ping Yin
  • View Affiliations

  • Published online on: April 10, 2019     https://doi.org/10.3892/mmr.2019.10148
  • Pages: 4890-4896
  • Copyright: © Bao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of this study was to investigate the protective effect of sulforaphane (SFN) on 1‑methyl‑4‑phenyl pyridine ion (MPP+)‑induced cytotoxicity and to investigate its possible mechanisms. Methods: PC12 cell toxicity induced by MPP+ served as a cell model of Parkinson's diseases. The cell culture + experiments were divided into four groups based on the different treatments, namely, vehicle control, SFN, MPP+ and SFN pretreatment plus MPP+. Cell viability and apoptosis were examined by MTT assay and flow cytometry, respectively. Expressions of nuclear factor erythroid 2‑related factor 2 (Nrf2), heme oxygenase 1 (HO‑1) and nicotinamide quinone oxidoreductase 1 (NQO1) were detected using western blotting. Results: MPP+ reduced the survival rate of PC12 cells in a dose‑ and time‑dependent manner. After 24‑h treatment with 500 µmol/l MPP+, the survival rate of PC12 cells decreased to 58.2±0.03% of that in the control groups. Under the same conditions MPP+ resulted in significant apoptosis of PC12 cells (apoptosis rate: 30.4±0.6%). However, SFN pretreatment significantly attenuated the cell damage induced by MPP+. Furthermore, it was demonstrated that SFN reversed the reduction of Nrf2, HO‑1 and NQO1 expression induced by MPP+. Conclusion: SFN may protect PC12 cells from MPP+‑induced damage via activating the Nrf2‑ARE (antioxidant responsive element) pathway.

References

1 

Dauer W and Przedborski S: Parkinson's disease: Mechanisms and models. Neuron. 39:889–909. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Tolleson CM and Fang JY: Advances in the mechanisms of Parkinson's disease. Discov Med. 15:61–66. 2013.PubMed/NCBI

3 

Coyle JT and Puttfarcken P: Oxidative stress, glutamate, and neurodegenerative disorders. Science. 262:689–695. 1993. View Article : Google Scholar : PubMed/NCBI

4 

Zhou C, Huang Y and Przedborski S: Oxidative stress in Parkinson's disease: A mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci. 1147:93–104. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Liu Z, Zhou T, Ziegler AC, Dimitrion P and Zuo L: Oxidative stress in neurodegenerative diseases: From molecular mechanisms to clinical applications. Oxid Med Cell Longev. 2017:25259672017. View Article : Google Scholar : PubMed/NCBI

6 

Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A and Puigserver P: GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 3:429–438. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Jha N, Kumar MJ, Boonplueang R and Andersen JK: Glutathione decreases in dopaminergic PC12 cells interfere with the ubiquitin protein degradation pathway: Relevance for Parkinson's disease? J Neurochem. 80:555–561. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Wang JJ, Zhang T, Niu DB, Wang K, Li KR, Xue B and Wang XM: Doxycycline-regulated co-expression of GDNF and TH in PC12 cells. Neurosci Lett. 401:142–145. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Liu Y, Liu L, Ying XX, Wei WJ, Han C, Liu Y, Han CH, Leng AJ, Ma JY and Liu J: Dried rehmannia root protects against glutamate-induced cytotoxity to PC12 cells through energy metabolism-related pathways. Neural Regen Res. 12:1338–1346. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Soane L, Li Dai W, Fiskum G and Bambrick LL: Sulforaphane protects immature hippocampal neurons against death caused by exposure to hemin or to oxygen and glucose deprivation. J Neurosci Res. 88:1355–1363. 2010.PubMed/NCBI

11 

Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, Conney AH and Kong AN: Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res. 66:8293–8296. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Fisher ML, Ciavattone N, Grun D, Adhikary G and Eckert RL: Sulforaphane reduces YAP/ΔNp63α signaling to reduce cancer stem cell survival and tumor formation. Oncotarget. 8:73407–73418. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Kubo E, Chhunchha B, Singh P, Sasaki H and Singh DP: Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress. Sci Rep. 7:141302017. View Article : Google Scholar : PubMed/NCBI

14 

Thejass P and Kuttan G: Immunomodulatory activity of sulforaphane, a naturally occurring isothiocyanate from broccoli (Brassica oleracea). Phytomedicine. 14:538–545. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Greaney AJ, Maier NK, Leppla SH and Moayeri M: Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism. J Leukoc Biol. 99:189–199. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Dwivedi S, Rajasekar N, Hanif K, Nath C and Shukla R: Sulforaphane ameliorates okadaic acid-induced memory impairment in rats by activating the Nrf2/HO-1 antioxidant pathway. Mol Neurobiol. 53:5310–5323. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Jang M and Cho IH: Sulforaphane ameliorates 3-nitropropionic acid-induced striatal toxicity by activating the keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-κB pathways. Mol Neurobiol. 53:2619–2635. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Minelli A, Conte C, Cacciatore I, Cornacchia C and Pinnen F: Molecular mechanism underlying the cerebral effect of Gly-Pro-Glu tripeptide bound to L-dopa in a Parkinson's animal model. Amino Acids. 43:1359–1367. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW and Johnson JA: Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci USA. 106:2933–2938. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Yin XP, Chen ZY, Zhou J, Wu D and Bao B: Mechanisms underlying the perifocal neuroprotective effect of the Nrf2-ARE signaling pathway after intracranial hemorrhage. Drug Des Devel Ther. 9:5973–5986. 2015.PubMed/NCBI

21 

Yin XP, Wu D, Zhou J, Chen ZY, Bao B and Xie L: Heme oxygenase 1 plays role of neuron-protection by regulating Nrf2-ARE signaling post intracerebral hemorrhage. Int J Clin Exp Pathol. 8:10156–10163. 2015.PubMed/NCBI

22 

Chen G, Fang Q, Zhang J, Zhou D and Wang Z: Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res. 89:515–523. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Rostamian Delavar M, Baghi M, Safaeinejad Z, Kiani-Esfahani A, Ghaedi K and Nasr-Esfahani MH: Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson's disease. Gene. 662:54–65. 2018. View Article : Google Scholar : PubMed/NCBI

24 

Cheng W, Chen W, Wang P and Chu J: Asiatic acid protects differentiated PC12 cells from Aβ25-35-induced apoptosis and tau hyperphosphorylation via regulating PI3K/Akt/GSK-3β signaling. Life Sci. 208:96–101. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Yin X, Zhang X, Wang W, Chang L, Jiang Y and Zhang S: Perihematoma damage at different time points in experimental intracerebral hemorrhage. J Huazhong Univ Sci Technolog Med Sci. 26:59–62. 2006. View Article : Google Scholar : PubMed/NCBI

26 

Yin M, Chen Z, Ouyang Y, Zhang H, Wan Z, Wang H, Wu W and Yin X: Thrombin-induced, TNFR-dependent miR-181c downregulation promotes MLL1 and NF-κB target gene expression in human microglia. J Neuroinflammation. 14:1322017. View Article : Google Scholar : PubMed/NCBI

27 

Kajimura Y, Aoki T, Kuramochi K, Kobayashi S, Sugawara F, Watanabe N and Arai T: Neoechinulin A protects PC12 cells against MPP+-induced cytotoxicity. J Antibiot (Tokyo). 61:330–333. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Lu XL, Lin YH, Wu Q, Su FJ, Ye CH, Shi L, He BX, Huang FW, Pei Z and Yao XL: Paeonolum protects against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells. BMC Complement Altern Med. 15:1372015. View Article : Google Scholar : PubMed/NCBI

29 

Houghton CA, Fassett RG and Coombes JS: Sulforaphane and other nutrigenomic Nrf2 activators: Can the clinician's expectation be matched by the reality? Oxid Med Cell Longev. 2016:78571862016. View Article : Google Scholar : PubMed/NCBI

30 

Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J and Johnson JA: The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 11:497–508. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Gilgun-Sherki Y, Rosenbaum Z, Melamed E and Offen D: Antioxidant therapy in acute central nervous system injury: Current state. Pharmacol Rev. 54:271–284. 2002. View Article : Google Scholar : PubMed/NCBI

32 

Hartley A, Stone JM, Heron C, Cooper JM and Schapira AH: Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: Relevance to Parkinson's disease. J Neurochem. 63:1987–1990. 1994. View Article : Google Scholar : PubMed/NCBI

33 

Zhang L, Huang L, Li X, Liu C, Sun X, Wu L, Li T, Yang H and Chen J: Potential molecular mechanisms mediating the protective effects of tetrahydroxystilbene glucoside on MPP+-induced PC12 cell apoptosis. Mol Cell Biochem. 436:203–213. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Ye S, Koon HK, Fan W, Xu Y, Wei W, Xu C and Cai J: Effect of a traditional chinese herbal medicine formulation on cell survival and apoptosis of MPP+-treated MES 23.5 dopaminergic cells. Parkinsons Dis. 2017:47642122017.PubMed/NCBI

35 

Zhang Z, Li C, Shang L, Zhang Y, Zou R, Zhan Y and Bi B: Sulforaphane induces apoptosis and inhibits invasion in U251MG glioblastoma cells. Springerplus. 5:2352016. View Article : Google Scholar : PubMed/NCBI

36 

Żuryń A, Litwiniec A, Safiejko-Mroczka B, Klimaszewska- Wiśniewska A, Gagat M, Krajewski A, Gackowska L and Grzanka D: The effect of sulforaphane on the cell cycle, apoptosis and expression of cyclin D1 and p21 in the A549 non-small cell lung cancer cell line. Int J Oncol. 48:2521–2533. 2016. View Article : Google Scholar : PubMed/NCBI

37 

Pledgie-Tracy A, Sobolewski MD and Davidson NE: Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther. 6:1013–1021. 2007. View Article : Google Scholar : PubMed/NCBI

38 

An YW, Jhang KA, Woo SY, Kang JL and Chong YH: Sulforaphane exerts its anti-inflammatory effect against amyloid-β peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages. Neurobiol Aging. 38:1–10. 2016. View Article : Google Scholar : PubMed/NCBI

39 

Pearson BL, Simon JM, McCoy ES, Salazar G, Fragola G and Zylka MJ: Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat Commun. 7:111732016. View Article : Google Scholar : PubMed/NCBI

40 

Chirumbolo S and Bjørklund G: Sulforaphane and 5-fluorouracil synergistically inducing autophagy in breast cancer: A possible role for the Nrf2-Keap1-ARE signaling? Food Chem Toxicol. 2018. View Article : Google Scholar

41 

Wang F, Wang W, Li J, Zhang J, Wang X and Wang M: Sulforaphane reverses gefitinib tolerance in human lung cancer cells via modulation of sonic hedgehog signaling. Oncol Lett. 15:109–114. 2018.PubMed/NCBI

42 

Ramirez CN, Li W, Zhang C, Wu R, Su S, Wang C, Gao L, Yin R and Kong AN: In vitro-in vivo dose response of ursolic acid, sulforaphane, PEITC, and curcumin in cancer prevention. AAPS J. 20:192017. View Article : Google Scholar : PubMed/NCBI

43 

Evans PC: The influence of sulforaphane on vascular health and its relevance to nutritional approaches to prevent cardiovascular disease. EPMA J. 2:9–14. 2011. View Article : Google Scholar : PubMed/NCBI

44 

Nagata N, Xu L, Kohno S, Ushida Y, Aoki Y, Umeda R, Fuke N, Zhuge F, Ni Y, Nagashimada M, et al: Glucoraphanin ameliorates obesity and insulin resistance through adipose tissue browning and reduction of metabolic endotoxemia in mice. Diabetes. 66:1222–1236. 2017. View Article : Google Scholar : PubMed/NCBI

45 

Brown RH, Reynolds C, Brooker A, Talalay P and Fahey JW: Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways. Respir Res. 16:1062015. View Article : Google Scholar : PubMed/NCBI

46 

Xin Y, Bai Y, Jiang X, Zhou S, Wang Y, Wintergerst KA, Cui T, Ji H, Tan Y and Cai L: Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway. Redox Biol. 15:405–417. 2018. View Article : Google Scholar : PubMed/NCBI

47 

Stepniewski J, Pacholczak T, Skrzypczyk A, Ciesla M, Szade A, Szade K, Bidanel R, Langrzyk A, Grochowski R, Vandermeeren F, et al: Heme oxygenase-1 affects generation and spontaneous cardiac differentiation of induced pluripotent stem cells. IUBMB Life. 70:129–142. 2018. View Article : Google Scholar : PubMed/NCBI

48 

Dinkova-Kostova AT, Fahey JW, Kostov RV and Kensler TW: KEAP1 and done? targeting the NRF2 pathway with sulforaphane. Trends Food Sci Technol. 69:257–269. 2017. View Article : Google Scholar : PubMed/NCBI

49 

Izumi Y, Kataoka H, Inose Y, Akaike A, Koyama Y and Kume T: Neuroprotective effect of an Nrf2-ARE activator identified from a chemical library on dopaminergic neurons. Eur J Pharmacol. 818:470–479. 2018. View Article : Google Scholar : PubMed/NCBI

50 

Cho JH, Kim YW and Keum YS: Sulforaphane suppresses LPS-induced or TPA-induced downregulation of PDCD4 in RAW 264.7 cells. Phytother Res. 28:1606–1611. 2014. View Article : Google Scholar : PubMed/NCBI

51 

Ma Q: Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 53:401–426. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY and Kleeberger SR: Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol. 26:175–182. 2002. View Article : Google Scholar : PubMed/NCBI

53 

Mastrangelo L, Cassidy A, Mulholland F, Wang W and Bao Y: Serotonin receptors, novel targets of sulforaphane identified by proteomic analysis in Caco-2 cells. Cancer Res. 68:5487–5491. 2008. View Article : Google Scholar : PubMed/NCBI

54 

Lee S and Kim J, Seo SG, Choi BR, Han JS, Lee KW and Kim J: Sulforaphane alleviates scopolamine-induced memory impairment in mice. Pharmacol Res. 85:23–32. 2014. View Article : Google Scholar : PubMed/NCBI

55 

Chinaglia G, Alvarez FJ, Probst A and Palacios JM: Mesostriatal and mesolimbic dopamine uptake binding sites are reduced in Parkinson's disease and progressive supranuclear palsy: A quantitative autoradiographic study using [3H]mazindol. Neuroscience. 49:317–327. 1992. View Article : Google Scholar : PubMed/NCBI

56 

Leenders KL, Salmon EP, Tyrrell P, Perani D, Brooks DJ, Sager H, Jones T, Marsden CD and Frackowiak RS: The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease. Arch Neurol. 47:1290–1298. 1990. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Bao, B., Zhang, M., Chen, Z., Wu, X., Xia, Z., Chai, J., & Yin, X. (2019). Sulforaphane prevents PC12 cells from oxidative damage via the Nrf2 pathway. Molecular Medicine Reports, 19, 4890-4896. https://doi.org/10.3892/mmr.2019.10148
MLA
Bao, B., Zhang, M., Chen, Z., Wu, X., Xia, Z., Chai, J., Yin, X."Sulforaphane prevents PC12 cells from oxidative damage via the Nrf2 pathway". Molecular Medicine Reports 19.6 (2019): 4890-4896.
Chicago
Bao, B., Zhang, M., Chen, Z., Wu, X., Xia, Z., Chai, J., Yin, X."Sulforaphane prevents PC12 cells from oxidative damage via the Nrf2 pathway". Molecular Medicine Reports 19, no. 6 (2019): 4890-4896. https://doi.org/10.3892/mmr.2019.10148