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

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.

Exogenous hydrogen sulfide mitigates NLRP3 inflammasome-mediated inflammation through promoting autophagy via AMPK-mTOR pathway

“…In recent years, it has been found that autophagy is closely related to the protective effect of H 2 S. Pretreatment with NaHS could alleviate acute myocardial ischemia injury by suppressing autophagy under oxidative stress, significantly reducing brain damage and preserving the blood-brain barrier integrity after traumatic brain injury by inhibiting autophagy via activation of the PI3K/Akt/mTOR signaling pathway and mitigating acrylonitrile-induced decrease of cell viability through influencing autophagy (Bai et al, 2018; Xu et al, 2018; Yang et al, 2018). Exogenous H 2 S also might protect mouse kidney against unilateral ureteral obstruction by suppressing ROS-AMPK-mediated autophagy, ameliorating blood-spinal cord barrier disruption and improving functional recovery by suppressing endoplasmic reticulum stress-mediated autophagy and inducing the apoptosis of hepatocellular carcinoma cells through promoting autophagy via the PI3K/AKT/mTOR signaling pathway (Chen et al, 2018a,b; Wang et al, 2017, 2018). Autophagy has also been reported to be closely related to NLRP3 inflammasome-mediated inflammation.…”

Sodium Tanshinone IIA Sulfonate Promotes Spinal Cord Injury Repair by Inhibiting BSCB Disruption In Vitro and In Vivo

“…1C). The TJ and AJ proteins between SCMECs maintain the barrier function of BSCB, and their loss is directly related to increased permeability [30]. As shown in Fig.…”

Insulin‑like growth factor 1 promotes neurological functional recovery after spinal cord injury through inhibition of autophagy via the PI3K/Akt/mTOR signaling pathway

“…The intensity, timing and regulating mechanisms underlying autophagy may have protective effects or may aggravate damage in cells ( 20 , 51 ). At present, it is recognized that autophagy is increased following SCI ( 52 , 53 ). However, it has been demonstrated by various studies that the same interference may lead to different outcomes ( 18 ).…”