Research Paper Volume 11, Issue 24 pp 12032—12042

Compound 13 activates AMPK-Nrf2 signaling to protect neuronal cells from oxygen glucose deprivation-reoxygenation

Yanqing Mo 1, *, , Jian-liang Zhu 2, *, , Aihua Jiang 1, *, , Jing Zhao 1, , Liping Ye 1, , Bin Han 1, ,

  • 1 Minhang Hospital, Fudan University, Minhang District, Shanghai, China
  • 2 Department of Emergency and Intensive Care Unit, The Second Affiliated Hospital of Soochow University, Suzhou, China
* Co-first authors

received: September 7, 2019 ; accepted: November 18, 2019 ; published: December 18, 2019 ;

https://doi.org/10.18632/aging.102534
How to Cite

Copyright © 2019 Mo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Oxygen glucose deprivation-reoxygenation (OGD-R) causes the production of reactive oxygen species (ROS) and oxidative injury in neuronal cells. We tested the potential neuroprotective function of compound 13 (C13), a novel AMP-activated protein kinase (AMPK) activator, against OGD-R. We show that C13 pretreatment protected SH-SY5Y neuronal cells and primary hippocampal neurons from OGD-R. C13 activated AMPK signaling in SH-SY5Y cells and primary neurons. It significantly inhibited OGD-R-induced apoptosis activation in neuronal cells. Conversely, AMPKα1 shRNA or knockout reversed C13-mediated neuroprotection against OGD-R. C13 potently inhibited OGD-R-induced ROS production and oxidative stress in SH-SY5Y cells and primary neurons. Furthermore, C13 induced Keap1 downregulation and Nrf2 activation, causing Nrf2 stabilization, nuclear accumulation, and expression of Nrf2-dependent genes. Nrf2 silencing or knockout in SH-SY5Y cells abolished C13-mediated neuroprotection against OGD-R. In conclusion, C13 activates AMPK-Nrf2 signaling to protect neuronal cells from OGD-R.

Abbreviations

AMPK: AMP-activated protein kinase; CCK-8: Cell Counting Kit-8; C13: compound 13; DMEM: Dulbecco’s modified Eagle’s medium; ELISA: enzyme-linked immunosorbent assay; LDH: lactate dehydrogenase; NADPH: nicotinamide adenine dinucleotide phosphate; Nrf2: nuclear factor erythroid 2-related factor 2; OGD: oxygen glucose deprivation; OGD-R: oxygen glucose deprivation-reoxygenation; OD: optical density; ROS: reactive oxygen species; shRNA: short hairpin RNA; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling.