Hydrogen Sulfide Ameliorates Blood-Spinal Cord Barrier Disruption and Improves Functional Recovery by Inhibiting Endoplasmic Reticulum Stress-Dependent Autophagy.

Haoli Wang,Ling Xie,Huazi Xu,Wen Han,Zhengmao Li,Qingqing Wang,Huacheng He,Yanlong Liu,Jiawei Li,Kebin Xu,Jian Xiao,Jiang Wu,Yanqing Wu,Ke Xu

doi:10.3389/fphar.2018.00858

Abstract

Spinal cord injury (SCI) induces the disruption of blood-spinal cord barrier (BSCB), which elicits neurological deficits by triggering secondary injuries. Hydrogen sulfide (H2S) is a gaseous mediator that has been reported to have neuroprotective effect in the central nervous system. However, the relationship between H2S and BSCB disruption during SCI remains unknown. Therefore, it is interesting to evaluate whether the administration of NaHS, a H2S donor, can protect BSCB integrity against SCI and investigate the potential mechanisms underlying it. In present study, we found that SCI markedly activated endoplasmic reticulum (ER) stress and autophagy in a rat model of complete crushing injury to the spinal cord at T9 level. NaHS treatment prevented the loss of tight junction (TJ) and adherens junction (AJ) proteins both in vivo and in vitro. However, the protective effect of NaHS on BSCB restoration was significantly reduced by an ER stress activator (tunicamycin, TM) and an autophagy activator (rapamycin, Rapa). Moreover, SCI-induced autophagy was remarkably blocked by the ER stress inhibitor (4-phenylbutyric acid, 4-PBA). But the autophagy inhibitor (3-Methyladenine, 3-MA) only inhibited autophagy without obvious effects on ER stress. Finally, we had revealed that NaHS significantly alleviated BSCB permeability and improved functional recovery after SCI, and these effects were markedly reversed by TM and Rapa. In conclusion, our present study has demonstrated that NaHS treatment is beneficial for SCI recovery, indicating that H2S treatment is a potential therapeutic strategy for promoting SCI recovery.

Highlights

The blood-spinal cord barrier (BSCB) is primarily composed of a specialized system of endothelial cells (ECs) and accessory structures, including the basement membrane, astrocytic end feet processes and pericytes
To detect whether endoplasmic reticulum (ER) stress and autophagy were involved in Spinal cord injury (SCI), we had detected the expression levels of ER stress makers (GRP78 and PDI) and autophagy makers (LC3 and Beclin-1) in a rat model of SCI
It was observed that the levels of GRP78, PDI, p-JNK, ATF6, CHOP, and Cle-Caspase 12 were significantly increased after SCI, and those increases were markedly inhibited by NaHS treatment (Figures 2A,B)

Summary

Introduction

The blood-spinal cord barrier (BSCB) is primarily composed of a specialized system of endothelial cells (ECs) and accessory structures, including the basement membrane, astrocytic end feet processes and pericytes. BSCB forms a tight structure owing to the well-developed tight junctions (TJs) proteins and adherens junctions (AJs) proteins that block the entry of molecules into the spinal cord (Bartanusz et al, 2011; Zheng et al, 2017). Recent studies have demonstrated that H2S plays a crucial role in physiological and biological effects (Abe and Kimura, 1996; Fiorucci et al, 2006; Martelli et al, 2012). H2S has been demonstrated to ameliorate homocysteine-induced brain blood barrier disruption in mice (Kamat et al, 2016). It is unclear whether H2S plays a role in protecting BSCB integrity after SCI

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Results

Conclusion