Neurochemical Research

, Volume 39, Issue 9, pp 1759–1766 | Cite as

The Neuroprotective Effects of α-Iso-cubebene on Dopaminergic Cell Death: Involvement of CREB/Nrf2 Signaling

  • Sun Young Park
  • Beung Gu Son
  • Young Hoon Park
  • Cheol-Min Kim
  • Geuntae Park
  • Young-Whan Choi
Original Paper


As a part of ongoing studies to elucidate pharmacologically active components of Schisandra chinensis, we isolated and studied α-iso-cubebene. The neuroprotective mechanisms of α-iso-cubebene in human neuroblastoma SH-SY5Y cells were investigated. α-Iso-cubebene significantly inhibited cytotoxicity and apoptosis due to 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in dopaminergic SH-SY5Y cells. Pretreatment of cells with α-iso-cubebene reduced intracellular accumulation of ROS and calcium in response to 6-OHDA. The neuroprotective effects of α-iso-cubebene were found to result from protecting the mitochondrial membrane potential. Notably, α-iso-cubebene inhibited the release of apoptosis-inducing factor from the mitochondria into the cytosol and nucleus after 6-OHDA treatment. α-Iso-cubebene also induced the activation of PKA/PKB/CREB/Nrf2 and suppressed 6-OHDA-induced neurotoxicity. α-Iso-cubebene was found to induce phosphorylation of PKA and PKB and activate Nrf2 and CREB signaling pathways in a dose-dependent manner. Additionally, α-iso-cubebene stimulated the expression of the antioxidant response genes NQO1 and HO-1. Finally, α-iso-cubebene-mediated neuroprotective effects were found to be reversible after transfection with CREB and Nrf2 small interfering RNAs.


α-Iso-cubebene Dopaminergic neurotoxicant Oxidative stress Apoptosis CREB Nrf2 



This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A3010601).


  1. 1.
    Martin I, Dawson VL, Dawson TM (2011) Recent advances in the genetics of parkinson’s disease. Annu Rev Genomics Hum Genet 12:301–325PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of parkinson disease: molecules to medicine. J Clin Invest 116:1744–1754PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Tobon-Velasco JC, Limon-Pacheco JH, Orozco-Ibarra M et al (2013) 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-kappaB factors. Toxicology 304:109–119PubMedCrossRefGoogle Scholar
  4. 4.
    Glinka Y, Gassen M, Youdim MB (1997) Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm Suppl 50:55–66PubMedCrossRefGoogle Scholar
  5. 5.
    Hong SJ, Dawson TM, Dawson VL (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci 25:259–264PubMedCrossRefGoogle Scholar
  6. 6.
    Bove J, Perier C (2012) Neurotoxin-based models of parkinson’s disease. Neuroscience 211:51–76PubMedCrossRefGoogle Scholar
  7. 7.
    Cheng JC, Esparza S, Sandoval S et al (2007) Potential role of CREB as a prognostic marker in acute myeloid leukemia. Future Oncol 3:475–480PubMedCrossRefGoogle Scholar
  8. 8.
    Katoh Y, Itoh K, Yoshida E et al (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6:857–868PubMedCrossRefGoogle Scholar
  9. 9.
    Lee J, Kim CH, Simon DK et al (2005) Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival. J Biol Chem 280:40398–40401PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Park SY, Kim JH, Lee SJ et al (2013) Involvement of PKA and HO-1 signaling in anti-inflammatory effects of surfactin in BV-2 microglial cells. Toxicol Appl Pharmacol 268:68–78PubMedCrossRefGoogle Scholar
  11. 11.
    Baxter PS, Martel MA, McMahon A et al (2011) Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1. J Neurochem 118:365–378PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Nakaso K, Ito S, Nakashima K (2008) Caffeine activates the PI3 K/akt pathway and prevents apoptotic cell death in a parkinson’s disease model of SH-SY5Y cells. Neurosci Lett 432:146–150PubMedCrossRefGoogle Scholar
  13. 13.
    Schapira AH, Gegg M (2011) Mitochondrial contribution to parkinson’s disease pathogenesis. Parkinsons Dis 2011:159160PubMedCentralPubMedGoogle Scholar
  14. 14.
    Lee SK, Kim SD, Lee HY et al (2012) Alpha-iso-cubebene, a natural compound isolated from Schisandra chinensis fruit, has therapeutic benefit against polymicrobial sepsis. Biochem Biophys Res Commun 426:226–231PubMedCrossRefGoogle Scholar
  15. 15.
    Park SY, Park SJ, Park NJ et al (2013) Alpha-iso-cubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation. Neurosci Lett 555:143–148PubMedCrossRefGoogle Scholar
  16. 16.
    Lee YJ, Shim JW, Lee YJ et al (2009) Identification of a novel compound that stimulates intracellular calcium increase and CXCL8 production in human neutrophils from Schisandra chinensis. Biochem Biophys Res Commun 379:928–932PubMedCrossRefGoogle Scholar
  17. 17.
    Presgraves SP, Ahmed T, Borwege S et al (2004) Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists. Neurotox Res 5:579–598PubMedCrossRefGoogle Scholar
  18. 18.
    Schneider L, Giordano S, Zelickson BR et al (2011) Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress. Free Radic Biol Med 51:2007–2017PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gorman AM, Orrenius S, Ceccatelli S (1998) Apoptosis in neuronal cells: role of caspases. NeuroReport 9:R49–R55PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang H, Wang ZQ, Zhao DY et al (2011) AIF-mediated mitochondrial pathway is critical for the protective effect of diazoxide against SH-SY5Y cell apoptosis. Brain Res 1370:89–98PubMedCrossRefGoogle Scholar
  21. 21.
    Kawai Y, Garduno L, Theodore M et al (2011) Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem 286:7629–7640PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sun Young Park
    • 1
  • Beung Gu Son
    • 2
  • Young Hoon Park
    • 2
  • Cheol-Min Kim
    • 3
  • Geuntae Park
    • 1
    • 4
  • Young-Whan Choi
    • 5
    • 6
  1. 1.Bio-IT Fusion Technology Research InstitutePusan National UniversityBusanKorea
  2. 2.Department of Horticultural BiosciencePusan National UniversityMiryangKorea
  3. 3.Research Center for Anti-Aging Technology DevelopmentPusan National UniversityBusanKorea
  4. 4.Department of Nanomaterials EngineeringPusan National UniversityBusanKorea
  5. 5.Life and Industry Convergence Research InstitutePusan National UniversityMiryangKorea
  6. 6.Department of Horticultural BiosciencePusan National UniversityMiryangKorea

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