Planta Med 2016; 82(S 01): S1-S381
DOI: 10.1055/s-0036-1596894
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

Protective effect of ECN against oxidative stress is mediated by Nrf2 signaling pathway in PC12 cells: therapeutic strategy for neurodegenerative diseases

J Lee
1   College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea
,
U Kang
2   College of Pharmacy, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, South Korea
,
KH Song
1   College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea
,
EK Seo
2   College of Pharmacy, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, South Korea
,
YS Kim
1   College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea
› Author Affiliations
Further Information

Publication History

Publication Date:
14 December 2016 (online)

 

Oxidative stress plays a key role in neurodegenerative diseases such as Alzheimer and Parkinson's diseases. Therefore, the nuclear factor-E2-related factor 2 (Nrf2), a key regulator of antioxidative response, is considered to be important as a therapeutic target for neurodegenerative diseases[1]. We investigated the underlying mechanism of Nrf2-mediated neuroprotective effects against hydrogen peroxide (H2O2)-induced oxidative stress in PC12 cell line by 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), one of the sesquiterpenoids in Farfarae Flos. Hydrogen peroxide (H2O2) treatment for 24h decreased cell viability by 56.9%, while pretreatment PC12 cells with ECN had protective effect against H2O2-induced cytotoxicity by increasing cell viability up to 91.8%. ECN upregulated the ARE-luciferase activity (3.5-fold at 10µM), and induced the mRNA expression of Nrf2 and antioxidant enzyme heme oxygenase-1 (HO-1), showing 3.3- and 5.2-fold increase, respectively. Knockdown of Nrf2 by small interfering RNA (siRNA) abrogated upregulation of HO-1, indicating that ECN induced HO-1 via the Nrf2 pathway. Pretreatment with the thiol reducing agents, N-acetylcysteine (NAC) or dithiothreitol (DTT) attenuated Nrf2 activation and HO-1 expression, however, non-thiol reducing antioxidant, trolox failed to inhibit HO-1 induction by ECN. These results suggest that ECN may directly interact with Kelch-like ECH-associated protein 1 (Keap1) and modify critical cysteine thiols present in the proteins responsible for Nrf2-mediated upregulation of HO-1. Taken together, ECN exerts a neuroprotective effect against oxidative stress in PC12 cells, and this effect is mediated by the activation of Nrf2 signaling pathway. Thus, ECN, targeting Nrf2 activation and Nrf2-mediated cytoprotection, may be a promising therapeutic candidate as a novel Nrf2 activator for the development of neuroprotective agents derived from medicinal plants.

Acknowledgements: This work was supported by grants from the National Research Foundation of Korea (NRF-2013R1A1A2A10005492).

Keywords: Neuroprotection, PC12, Nrf2, HO-1, Tussilago farfara.

References:

[1] Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A 2009; 106: 2933 – 2938