β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38MAPK–p53 Signaling Pathway
- 550 Downloads
Parkinson’s disease (PD) is a neurological disorder pathologically characterized by loss of dopaminergic neurons in the substantia nigra. No curative therapy is available for PD. We recently found that phytoestrogen β-ecdysterone (β-Ecd) is able to reduce MPP+-induced apoptosis in PC12 cells. This study investigated the potential of β-Ecd to protect against SH-SY5Y cell apoptosis induced by the PD-related neurotoxin 6-hydroxydopamine (6-OHDA) and the underlying mechanism for this cytoprotection. In the present study, pretreatment with β-Ecd significantly reduced 6-OHDA-induced apoptosis of SH-SY5Y cells by a mitochondria-dependent pathway, as indicated by downregulation of Bax and PUMA (p53 upregulated modulator of apoptosis) expression, suppressing ΔΨm loss, inhibiting cytochrome c release, and attenuating caspase-9 activation. Furthermore, we showed that the inhibition of p38 mitogen-activated protein kinase (p38MAPK)-dependent p53 promoter activity contributed to the protection of SH-SY5Y cells from apoptosis, which was validated by the use of SB203580 or p38β dominant negative (DN) mutants. Additionally, knock-down apoptosis signal-regulating kinase 1 (ASK1) by specific shRNA and blockade reactive oxygen species (ROS) by pharmacological inhibitor competently prevented β-Ecd-mediated inhibition of p38MAPK and ASK1 phosphorylation, respectively. These data provide the first evidence that β-Ecd protects SH-SY5Y cells against 6-OHDA-induced apoptosis, possibly through mitochondria protection and p53 modulation via ROS-dependent ASK1–p38MAPK pathways. The neuroprotective effects of β-Ecd make it a promising candidate as a therapeutic agent for PD.
Keywordsβ-Ecdysterone Parkinson’s disease p38MAPK Apoptosis Mitochondrial membrane potential
This work was supported by the National Natural Science Foundation of China Grant 81373629 awarded to Miaoxian Dong. We thank Dr. Rongtian Wang for critical comments on the manuscript and Tianjiao Xu for secretarial help.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflict of interest.
- Bozi M, Papadimitriou D, Antonellou R, Moraitou M, Maniati M, Vassilatis DK, Papageorgiou SG, Leonardos A, Tagaris G, Malamis G, Theofilopoulos D, Kamakari S, Stamboulis E, Hadjigeorgiou GM, Athanassiadou A, Michelakakis H, Papadimitriou A, Gasser T, Stefanis L (2014) Genetic assessment of familial and early-onset Parkinson’s disease in a Greek population. Eur J Neurol 21:963–968CrossRefPubMedGoogle Scholar
- Gomez-Lazaro M, Galindo MF, Concannon CG, Segura MF, Fernandez-Gomez FJ, Llecha N, Comella JX, Prehn JH, Jordan J (2008) 6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. J Neurochem 104:1599–1612CrossRefPubMedGoogle Scholar
- Grison A, Mantovani F, Comel A, Agostoni E, Gustincich S, Persichetti F, Del Sal G (2011) Ser46 phosphorylation and prolyl-isomerase Pin1-mediated isomerization of p53 are key events in p53-dependent apoptosis induced by mutant huntingtin. Proc Natl Acad Sci USA 108:17979–17984CrossRefPubMedPubMedCentralGoogle Scholar
- Ju C, Hou L, Sun F, Zhang L, Zhang Z, Gao H, Wang L, Wang D, Lv Y, Zhao X (2015) Anti-oxidation and antiapoptotic effects of chondroitin sulfate on 6-hydroxydopamine-induced injury through the up-regulation of Nrf2 and inhibition of mitochondria-mediated pathway. Neurochem Res 40:1509–1519CrossRefPubMedGoogle Scholar
- Karunakaran S, Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, Seth P, Ravindranath V (2008) Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. J Neurosci 28:12500–12509CrossRefPubMedGoogle Scholar
- Kipp M, Karakaya S, Pawlak J, Araujo-Wright G, Arnold S, Beyer C (2006) Estrogen and the development and protection of nigrostriatal dopaminergic neurons: concerted action of a multitude of signals, protective molecules, and growth factors. Front Neuroendocrinol 27:376–390CrossRefPubMedGoogle Scholar
- Lee HJ, Han J, Jang Y, Kim SJ, Park JH, Seo KS, Jeong S, Shin S, Lim K, Heo JY, Kweon GR (2015) Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis. Biochem Biophys Res Commun 457:95–100CrossRefPubMedGoogle Scholar
- Mermillod M, Mondillon L, Rieu I, Devaux D, Chambres P, Auxiette C, Dalens H, Coulangeon LM, Jalenques I, Durif F (2014) Dopamine replacement therapy and deep brain stimulation of the subthalamic nuclei induce modulation of emotional processes at different spatial frequencies in Parkinson’s disease. J Parkinsons Dis 4:97–110PubMedGoogle Scholar
- Schwarz ST, Rittman T, Gontu V, Morgan PS, Bajaj N, Auer DP (2011) T1-weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson’s disease. Mov Disord 26(9):1633–1638. doi:10.1002/mds.23722. Epub 2011 Apr 12. Erratum in: Mov Disord 27:335Google Scholar