Oncotarget

Research Papers:

JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane

Lei Zhou, Zeyong Yang _, Xianfu Lu, Xingxing Li, Xiaohu An, Jing Chai, Qiling Yang, Shikai Yan and Yuanhai Li

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Oncotarget. 2017; 8:94009-94019. https://doi.org/10.18632/oncotarget.21505

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Abstract

Lei Zhou1,*, Zeyong Yang2,*, Xianfu Lu1, Xingxing Li1, Xiaohu An2, Jing Chai2, Qiling Yang2, Shikai Yan3 and Yuanhai Li1

1Department of Anesthesiology, First Affiliated Hospital of AnHui Medical University, Hefei 230022, PR China

2Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, PR China

3School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China

*These authors have contributed equally to this work

Correspondence to:

Zeyong Yang, email: [email protected]

Shikai Yan, email: [email protected]

Yuanhai Li, email: [email protected]

Keywords: fetal neural stem cells, emulsified isoflurane, apoptosis, JNK, neurotoxicity

Received: November 22, 2016     Accepted: September 13, 2017     Published: October 04, 2017

ABSTRACT

Isoflurane can provide both neuroprotection and neurotoxicity in various culture models and in rodent developing brains. Emulsified Isoflurane (EI) is an emulsion formulation of isoflurane, while its underlying molecular mechanism of developemental nerve toxicity largely remains unclear. We hypothesized that EI induced fetal neural stem cells (FNSCs) apoptosis, endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation.

FNSCs were isolated from the cortex of SD rats during 14 days of gestation. The cell viability, cell apoptotic rates and the expression of apoptosis-related protein Caspase3, inositol requiring enzyme 1 (IRE1), poly (adenosine diphosphate-ribose) polymerase (PARP), Bax, Bcl-2, JNK, p-JNK and XBP1 were determined. Specific inhibition was performed by siRNA-targeting of JNK in FNSCs. EI could increase the p-JNK, JNK and caspase3 protein expression, the JNK pathway was activated by EI, and EI-induced apoptosis was blocked by inhibiting JNK pathway with SP600125 or JNK-small interfering RNA (siRNA), EI enhanced the level of IRE1, PARP, Bax/Bcl-2 and XBP1, which led FNSCs to apoptosis and ER stress. Meanwhile, dilatation of the ER lumens in FNSCs treated by EI for 24 h was significant. Green fluorescent protein (GFP) positive cell ratios were significantly decreased by FNSCs transfecting with JNK gene silencing. JNK was efficiently silenced in siRNA-JNK1 group.

The results provided in-vitro evidence which supports that the underlying mechanisms of EI-induced apoptosis are the induction of ER stress and sequent JNK activation. Together, these data suggest that JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity.

Highlights:

1. Prolonged treatment with high-dose EI decreased the survival level of FNSCs by inducing apoptosis and inhibiting proliferation via the JNK signaling pathway.

2. EI induced ER stress and sequent JNK activation.

3. JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity


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