Advertisement

Molecular and Cellular Biochemistry

, Volume 461, Issue 1–2, pp 81–89 | Cite as

SC79, a novel Akt activator, protects dopaminergic neuronal cells from MPP+ and rotenone

  • Jian-liang Zhu
  • Yu-ying Wu
  • Di Wu
  • Wei-Feng Luo
  • Zhi-qing ZhangEmail author
  • Chun-feng LiuEmail author
Article

Abstract

In pathogenesis of Parkinson’s disease (PD), mitochondrial dysfunction causes substantial reactive oxygen species (ROS) production and oxidative stress, leading to dopaminergic (DA) neuronal cell death. Mitochondrial toxins, including MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone, induce oxidative injury in cultured DA neuronal cells. The current study tested the potential effect of SC79, a first-in-class small-molecule Akt activator, against the process. In SH-SY5Y cells and primary murine DA neurons, SC79 significantly attenuated MPP+- and rotenone-induced viability reduction, cell death, and apoptosis. SC79 activated Akt signaling in DA neuronal cells. Akt inhibition (by LY294002 and MK-2206) or CRISPR-Cas9-mediated Akt1 knockout completely abolished SC79-induced DA neuroprotection against MPP+. Further studies demonstrated that SC79 attenuated MPP+- and rotenone-induced ROS production, mitochondrial depolarization, and lipid peroxidation in SH-SY5Y cells and primary DA neurons. Moreover, upregulation of Nrf2-dependent genes (HO1 and NQO1) and Nrf2 protein stabilization were detected in SC79-treated SH-SY5Y cells and primary DA neurons. Together we show that SC79 protects DA neuronal cells from mitochondrial toxins possibly via activation of Akt-Nrf2 signaling.

Keywords

Dopaminergic neuronal cells SC79 Akt Parkinson’s disease (PD) Nrf2 

Notes

Author contributions

All listed authors designed the study, performed the experiments and the statistical analysis, and wrote the manuscript. All authors have read the manuscript and approved the final version. Author D.W. performed the experiments in the primary neurons.

Funding

This work was supported by funds from a special project “diagnostic and therapeutic technology of key clinical diseases” of Suzhou (LCZX201404) and a grant from Suzhou Key Medicine Project Fund of China (Szxk201504) and a grant from National Natural Science Foundation of China (81502162).

Compliance with ethical standards

Conflict of interest

None of the authors have any competing interests.

References

  1. 1.
    Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219CrossRefGoogle Scholar
  2. 2.
    Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942CrossRefGoogle Scholar
  3. 3.
    Al Shahrani M, Heales S, Hargreaves I, Orford M (2017) Oxidative stress: mechanistic insights into inherited mitochondrial disorders and parkinson’s disease. J Clin Med 6(11):100CrossRefGoogle Scholar
  4. 4.
    Irwin DJ, Lee VM, Trojanowski JQ (2013) Parkinson’s disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat Rev Neurosci 14:626–636CrossRefGoogle Scholar
  5. 5.
    Ablat N, Lv D, Ren R, Xiaokaiti Y, Ma X, Zhao X, Sun Y, Lei H, Xu J, Ma Y, Qi X, Ye M, Xu F, Han H, Pu X (2016) Neuroprotective effects of a standardized flavonoid extract from safflower against a rotenone-induced rat model of parkinson’s disease. Molecules 21(9):1107CrossRefGoogle Scholar
  6. 6.
    Blesa J, Przedborski S (2014) Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 8:155CrossRefGoogle Scholar
  7. 7.
    Jo H, Mondal S, Tan D, Nagata E, Takizawa S, Sharma AK, Hou Q, Shanmugasundaram K, Prasad A, Tung JK, Tejeda AO, Man H, Rigby AC, Luo HR (2012) Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci USA 109:10581–10586CrossRefGoogle Scholar
  8. 8.
    Zheng K, Zhang Q, Lin G, Li Y, Sheng Z, Wang J, Chen L, Lu HH (2017) Activation of Akt by SC79 protects myocardiocytes from oxygen and glucose deprivation (OGD)/re-oxygenation. Oncotarget 8:14978–14987PubMedPubMedCentralGoogle Scholar
  9. 9.
    Li ST, Chen NN, Qiao YB, Zhu WL, Ruan JW, Zhou XZ (2016) SC79 rescues osteoblasts from dexamethasone though activating Akt-Nrf2 signaling. Biochem Biophys Res Commun 479:54–60CrossRefGoogle Scholar
  10. 10.
    Gong YQ, Huang W, Li KR, Liu YY, Cao GF, Cao C, Jiang Q (2016) SC79 protects retinal pigment epithelium cells from UV radiation via activating Akt-Nrf2 signaling. Oncotarget 7:60123–60132PubMedPubMedCentralGoogle Scholar
  11. 11.
    Xu Y, Gao YW, Yang Y (2018) SC79 protects dopaminergic neurons from oxidative stress. Oncotarget 9:12639–12648PubMedGoogle Scholar
  12. 12.
    Knaryan VH, Samantaray S, Park S, Azuma M, Inoue J, Banik NL (2014) SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone. J Neurochem 130:280–290CrossRefGoogle Scholar
  13. 13.
    Yuan WJ, Yasuhara T, Shingo T, Muraoka K, Agari T, Kameda M, Uozumi T, Tajiri N, Morimoto T, Jing M, Baba T, Wang F, Leung H, Matsui T, Miyoshi Y, Date I (2008) Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. BMC Neurosci 9:75CrossRefGoogle Scholar
  14. 14.
    Wu X, Liu D, Gao X, Xie F, Tao D, Xiao X, Wang L, Jiang G, Zeng F (2017) Inhibition of BRD4 suppresses cell proliferation and induces apoptosis in renal cell carcinoma. Cell Physiol Biochem 41:1947–1956CrossRefGoogle Scholar
  15. 15.
    Li KR, Zhang ZQ, Yao J, Zhao YX, Duan J, Cao C, Jiang Q (2013) Ginsenoside Rg-1 protects retinal pigment epithelium (RPE) cells from cobalt chloride (CoCl2) and hypoxia assaults. PLoS ONE 8:e84171CrossRefGoogle Scholar
  16. 16.
    Tang XF, Liu HY, Wu L, Li MH, Li SP, Xu HB (2017) Ginseng Rh2 protects endometrial cells from oxygen glucose deprivation/re-oxygenation. Oncotarget 8:105703–105713PubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu H, Feng Y, Xu M, Yang J, Wang Z, Di G (2018) Four-octyl itaconate activates Keap1-Nrf2 signaling to protect neuronal cells from hydrogen peroxide. Cell Commun Signal 16:81CrossRefGoogle Scholar
  18. 18.
    Zhu M, Li WW, Lu CZ (2014) Histone decacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection against MPP+. CNS Neurosci Ther 20:308–316CrossRefGoogle Scholar
  19. 19.
    Liu W, Mao L, Ji F, Chen F, Wang S, Xie Y (2017) Icariside II activates EGFR-Akt-Nrf2 signaling and protects osteoblasts from dexamethasone. Oncotarget 8:2594–2603PubMedGoogle Scholar
  20. 20.
    Zheng K, Sheng Z, Li Y, Lu H (2014) Salidroside inhibits oxygen glucose deprivation (OGD)/re-oxygenation-induced H9c2 cell necrosis through activating of Akt-Nrf2 signaling. Biochem Biophys Res Commun 451:79–85CrossRefGoogle Scholar
  21. 21.
    Zhang Y, Gong XG, Wang ZZ, Sun HM, Guo ZY, Hu JH, Ma L, Li P, Chen NH (2016) Overexpression of DJ-1/PARK7, the Parkinson’s disease-related protein, improves mitochondrial function via Akt phosphorylation on threonine 308 in dopaminergic neuron-like cells. Eur J Neurosci 43:1379–1388CrossRefGoogle Scholar
  22. 22.
    Bao XQ, Kong XC, Kong LB, Wu LY, Sun H, Zhang D (2014) Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson’s disease models. Brain Res 1547:49–57CrossRefGoogle Scholar
  23. 23.
    Kim SN, Kim ST, Doo AR, Park JY, Moon W, Chae Y, Yin CS, Lee H, Park HJ (2011) Phosphatidylinositol 3-kinase/Akt signaling pathway mediates acupuncture-induced dopaminergic neuron protection and motor function improvement in a mouse model of Parkinson’s disease. Int J Neurosci 121:562–569CrossRefGoogle Scholar
  24. 24.
    Wang R, Peng L, Zhao J, Zhang L, Guo C, Zheng W, Chen H (2015) Gardenamide A protects RGC-5 cells from H(2)O(2)-induced oxidative stress insults by activating PI3 K/Akt/eNOS signaling pathway. Int J Mol Sci 16:22350–22367CrossRefGoogle Scholar
  25. 25.
    Dong L, Zhou S, Yang X, Chen Q, He Y, Huang W (2013) Magnolol protects against oxidative stress-mediated neural cell damage by modulating mitochondrial dysfunction and PI3 K/Akt signaling. J Mol Neurosci 50:469–481CrossRefGoogle Scholar
  26. 26.
    Dal-Cim T, Molz S, Egea J, Parada E, Romero A, Budni J, Martin de Saavedra MD, del Barrio L, Tasca CI, Lopez MG (2012) Guanosine protects human neuroblastoma SH-SY5Y cells against mitochondrial oxidative stress by inducing heme oxigenase-1 via PI3 K/Akt/GSK-3beta pathway. Neurochem Int 61:397–404CrossRefGoogle Scholar
  27. 27.
    Mazo NA, Echeverria V, Cabezas R, Avila-Rodriguez M, Tarasov VV, Yarla NS, Aliev G, Barreto GE (2017) Medicinal plants as protective strategies against parkinson’s disease. Curr Pharm Des 23:4180–4188CrossRefGoogle Scholar
  28. 28.
    Yadav A, Agarwal S, Tiwari SK, Chaturvedi RK (2014) Mitochondria: prospective targets for neuroprotection in Parkinson’s disease. Curr Pharm Des 20:5558–5573CrossRefGoogle Scholar
  29. 29.
    Clark J, Simon DK (2009) Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson’s disease. Antioxid Redox Signal 11:509–528CrossRefGoogle Scholar
  30. 30.
    Lee YJ, Jeong HY, Kim YB, Won SY, Shim JH, Cho MK, Nam HS, Lee SH (2012) Reactive oxygen species and PI3 K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells. Food Chem Toxicol 50:116–123CrossRefGoogle Scholar
  31. 31.
    Xu Y, Duan C, Kuang Z, Hao Y, Jeffries JL, Lau GW (2013) Pseudomonas aeruginosa pyocyanin activates NRF2-ARE-mediated transcriptional response via the ROS-EGFR-PI3 K-AKT/MEK-ERK MAP kinase signaling in pulmonary epithelial cells. PLoS ONE 8:e72528CrossRefGoogle Scholar
  32. 32.
    Zhang H, Liu YY, Jiang Q, Li KR, Zhao YX, Cao C, Yao J (2014) Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling. Free Radic Biol Med 69:219–228CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Emergency and Intensive Care UnitThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Department of NeurologyThe Second Affiliated Hospital, Institute of Neuroscience, Soochow UniversitySuzhouChina
  3. 3.Institute of Neuroscience, Soochow UniversitySuzhouChina

Personalised recommendations