Oncotarget

Research Papers:

Targeting cyclophilin-D by compound 19 protects neuronal cells from oxygen glucose deprivation/re-oxygenation

Jinyu Zheng, Enhui Cui, Haikou Yang, Mao Li, Jing Zhou, Ming Yan, Jian Sun _ and De-Rong Tang

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Oncotarget. 2017; 8:90238-90249. https://doi.org/10.18632/oncotarget.21655

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Abstract

Jinyu Zheng1,*, Enhui Cui2,*, Haikou Yang2, Mao Li2, Jing Zhou2, Ming Yan2, Jian Sun2 and De-Rong Tang3

1Department of Neurosurgery, The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, China

2Department of Anesthesiology, Huai’an Maternity and Child Healthcare Hospital, Yangzhou University Medical School, Huai’an, China

3Department of Thoracic Surgery, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

*Co-first authors

Correspondence to:

Jian Sun, email: sunjianmzys@163.com

De-Rong Tang, email: tangderonglw@163.com

Keywords: oxygen glucose deprivation/re-oxygenation, cyclophilin-D, compound 19, programmed necrosis, P53

Received: July 25, 2017     Accepted: August 28, 2017     Published: October 06, 2017

ABSTRACT

Oxygen and glucose deprivation (OGD) with re-oxygenation (OGDR) is applied to neuronal cells to mimic ischemia-reperfusion injuries. Activation of cyclophilin D (Cyp-D)-dependent programmed necrosis pathway mediates OGDR-induced neuronal cell damages. Here, we tested the potential effect of Compound 19 (C19), a novel Cyp-D inhibitor, in this process. In both established neuronal cell lines (Neuro-2a and NB41A3 cells) and the primary murine CA1 hippocampal neurons, pretreatment with C19 largely attenuated OGDR-induced cell viability reduction and cell death. Significantly, C19 was ineffective in Cyp-D-silenced Neuro-2a cells. OGDR induced mitochondria-dependent programmed necrosis in neuronal cells. OGDR induced p53 translocation to mitochondria and association with Cyp-D, causing mitochondrial depolarization, cytochrome C release and reactive oxygen species production. Such effects were largely attenuated with pre-treatment of C19. Importantly, C19 was significantly more efficient than other known Cyp-D inhibitors in protecting neuronal cells from OGDR. These results suggest that targeting Cyp-D by C19 protects neuronal cells from OGDR.


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