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Research Paper|Volume 12, Issue 13|pp 13388—13399

PGK1 inhibitor CBR-470-1 protects neuronal cells from MPP+

Jinyu Zheng1, Jian-liang Zhu2, Yufeng Zhang3, Hao Zhang3, Yu Yang2, De-Rong Tang4, Jian Sun3
  • 1Department of Neurosurgery, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, China
  • 2Department of Emergency and Intensive Care Unit, The Second Affiliated Hospital of Soochow University, Suzhou, China
  • 3Department of Anesthesiology, Huai’an Maternity and Child Clinical College of Xuzhou Medical University, Huai’an, China
  • 4Department of Thoracic Surgery, The Affiliated Huaian People’s Hospital of Nanjing Medical University, Huai’an, China
* Co-first authors
Received: February 13, 2020Accepted: May 25, 2020Published: July 10, 2020
https://doi.org/10.18632/aging.103443

Copyright © 2020 Zheng 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

The neurotoxin MPP+ (1-methyl-4-phenylpyridinium ion) disrupts mitochondrial function leading to oxidative stress and neuronal death. Here we examine whether activation of the Keap1-Nrf2 cascade can protect SH-SY5Y neuroblastoma cells from MPP+-induced cytotoxicity. Treatment of SH-SY5Y cells with CBR-470-1, an inhibitor of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1), leads to methylglyoxal modification of Keap1, Keap1-Nrf2 disassociation, and increased expression of Nrf2 responsive genes. Pretreatment with CBR-470-1 potently attenuated MPP+-induced oxidative injury and SH-SY5Y cell apoptosis. CBR-470-1 neuroprotection is dependent upon Nrf2, as Nrf2 shRNA or CRISPR/Cas9-mediated Nrf2 knockout, abolished CBR-470-1-induced SH-SY5Y cytoprotection against MPP+. Consistent with these findings, PGK1 depletion or knockout mimicked CBR-470-1-induced actions and rendered SH-SY5Y cells resistant to MPP+-induced cytotoxicity. Furthermore, activation of the Nrf2 cascade by CRISPR/Cas9-induced Keap1 knockout protected SH-SY5Y cells from MPP+. In Keap1 or PGK1 knockout SH-SY5Y cells,CBR-470-1 failed to offer further cytoprotection against MPP+. Collectively PGK1 inhibition by CBR-470-1 protects SH-SY5Y cells from MPP+ via activation of the Keap1-Nrf2 cascade.