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Interdiscip Toxicol. 2017 Dec;10(4):129-141. doi: 10.1515/intox-2017-0019. Epub 2018 Mar 1.

Oleuropein and rutin protect against 6-OHDA-induced neurotoxicity in PC12 cells through modulation of mitochondrial function and unfolded protein response.

Author information

1
Department of Medical Pharmacology, Cellular Stress Response and Signal Transduction Research Laboratory, Gazi University, Faculty of Medicine, Ankara, Turkey.
2
Department of Medical Biology, Erzincan University, Faculty of Medicine, Erzincan, Turkey.
3
Department of Biology, Ankara University, Faculty of Science, Ankara, Turkey.
4
Department of Hematology, Gazi University, Faculty of Medicine, Ankara, Turkey.

Abstract

Parkinson's disease (PD) is a highly prevalent neurodegenerative disorder, often associated with oxidative stress-induced transcriptional changes in dopaminergic neurons. Phenolic antioxidants, oleuropein (OLE) and rutin (RUT) have attracted a great interest due to their potential to counteract oxidative protein aggregation and toxicity. This study aimed at examining the effects of OLE and RUT against 6-OHDA-induced stress response in rat pheochromocytoma cells. When differentiated PC12 cells were exposed to oxidative stress composer 6-OHDA (100 μM, 8 h), a decreased mitochondrial membrane potential (ΔΨm) was observed along with a significant loss of cell viability and apoptotic nuclear changes. Exposure to 6-OHDA resulted in unfolded protein response (UPR) in differentiated PC12 cells as evidenced by an increased level of endoplasmic reticulum (ER)-localized transmembrane signal transducer IRE1α, adaptive response proteins ATF-4 and proapoptotic transcription factor CHOP. OLE or RUT pretreatment (24 h) at low doses (1-50 μM) protected the differentiated PC12 cells from 6-OHDA-induced cytotoxicity as assessed by increased viability, improved ΔΨm and inhibited apoptosis, whereas relatively high doses of OLE or RUT (>50 μM) inhibited cell growth and proliferation, indicating a typical hormetic effect. In hormetic doses, OLE and RUT up-regulated 6-OHDA-induced increase in IRE1α, ATF-4 and inhibited CHOP, PERK, BIP and PDI. 6-OHDA-activated XBP1 splicing was also inhibited by OLE or RUT. The presented results suggest that neuroprotection against 6-OHDA-induced oxidative toxicity may be attributable to neurohormetic effects of OLE or RUT at low doses through regulating mitochondrial functions, controlling persistent protein misfolding, activating and/or amplificating the adaptive response-related signaling pathways, leading to UPR prosurvival output.

KEYWORDS:

endoplasmic reticulum; mitochondria; neurotoxicity; oleuropein; rutin

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