Zeng 2019 Toxicol Appl Pharmacol

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Zeng R, Wang X, Zhou Q, Fu X, Wu Q, Lu Y, Shi J, Klaunig JE, Zhou S (2019) Icariin protects rotenone-induced neurotoxicity through induction of SIRT3. Toxicol Appl Pharmacol 379:114639.

» PMID: 31251943

Zeng R, Wang X*, Zhou Q, Fu X, Wu Q, Lu Y, Shi J, Klaunig JE, Zhou S (2019) Toxicol Appl Pharmacol

Abstract: Sirtuin-3 (SIRT3) is a mitochondrial NAD + -dependent deacetylase that is essential in regulating mitochondrial proteins and maintaining cellular antioxidant properties. It has been reported that icariin (ICA) is neuroprotective over various neurotoxicant induced oxidative stress. This study aimed to determine whether ICA exerts neuroprotective effects on rotenone (ROT)-induced neurotoxicity through activation of SIRT3. Rats treated with ROT exhibited a marked loss of dopamine (DA) neurons and a decline in motor function, along with a decrease in protein expressions of SIRT3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the substantia nigra (SN). Administration of ICA significantly alleviated the loss of DA neurons, improved behavioral function, and concomitantly enhanced SIRT3 and PGC-1α expressions. The neuroprotective effect of ICA on ROT-induced cytotoxicity was further confirmed in the PC12 cell model, which showed significant improvement in the survival of ROT-treated cells with ICA pretreatment. The cytoprotective effect of ICA was abolished in ROT-treated cells by SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), along with a resultant decrease in PGC-1α expression. In addition, knockdown of PGC-1α by siRNA suppressed ICA-mediated protective effects but did not affect SIRT3 expression, indicating the role of regulation of PGC-1α by SIRT3 in the protective action of ICA. Furthermore, we showed that ICA improved mitochondrial respiration, oxidative status, enhanced antioxidant enzyme SOD activity and GSH/GSSG ratio in cells treated with ROT. However, these protective effects of ICA on ROT-treated cells was markedly abolished by SIRT3 inhibitor 3-TYP. Our findings demonstrate that ICA exerts a neuroprotective role through upregulation of SIRT3.

Copyright © 2018. Published by Elsevier Inc.

Keywords: Icariin, Mitochondrial dysfunction, Oxidative stress, PGC-1α, SIRT3 Bioblast editor: Plangger M

Labels: MiParea: Respiration, Pharmacology;toxicology 

Organism: Rat  Tissue;cell: Other cell lines  Preparation: Intact cells 

Regulation: Inhibitor 

HRR: Oxygraph-2k 

Labels, 2019-07