Inhibition of Endoplasmic Reticulum Stress Preserves the Integrity of Blood-Spinal Cord Barrier in Diabetic Rats Subjected to Spinal Cord Injury

Zili He,Zhengzheng Gao,Qingqing Wang,Yanqing Wu,Huacheng He,Jiayu Yin,Fenzan Wu,Jiawei Li,Yulong Zhou,Hua-Zi Xu,Shuang Zou,Yanlong Liu,Xiaofeng Jia,Jian Xiao

doi:10.1038/s41598-017-08052-4

Abstract

The blood-spinal cord barrier (BSCB) plays significance roles in recovery following spinal cord injury (SCI), and diabetes mellitus (DM) impairs endothelial cell function and integrity of BSCS. Endoplasmic reticulum (ER) stress occurs in the early stages of SCI and affects prognosis and cell survival. However, the relationship between ER stress and the integrity of BSCB in diabetic rats after SCI remains unclear. Here we observed that diabetic rats showed increased extravasation of Evans Blue (EB) dye, and loss of endothelial cells and pericytes 1 day after SCI compared to non-diabetic rats. Diabetes was also shown to induce activation of ER stress. Similar effects were observed in human brain microvascular endothelial cells. 4-phenylbutyric acid (4-PBA), an ER stress inhibitor lowered the adverse effect of diabetes on SCI, reduced EB dye extravasation, and limited the loss of endothelial cells and pericytes. Moreover, 4-PBA treatment partially reversed the degradation of tight junction and adherens junction both in vivo and in vitro. In conclusion, diabetes exacerbates the disruption of BSCB after SCI via inducing ER stress, and inhibition of ER stress by 4-PBA may play a beneficial role on the integrity of BSCB in diabetic SCI rats, leading to improved prognosis.

Highlights

Hyperglycemia facilitates a progressive impairment of neuronal function after spinal cord injury (SCI) in experimental animals and clinical practices[6, 7]
BBB and blood-spinal cord barrier (BSCB), which are composed of endothelial cells, astrocytes, pericytes and dense junction proteins, are tight barriers between the circulating blood and central nervous system (CNS)
Studies have demonstrated that diabetic SCI rats exhibit worse functional recovery, which indicate that diabetic animals will have worse prognoses than non-diabetic animals if the same severity of SCI was inflicted[15]

Summary

Introduction

Hyperglycemia facilitates a progressive impairment of neuronal function after SCI in experimental animals and clinical practices[6, 7]. Except for many studies on the effect of ER stress in neurons, astrocytes, oligodendrocytes, and microglia[20,21,22] after SCI, recently, little attention has been paid to the role of ER stress in endothelial cells and BSCB disruption after acute SCI23. Our previous studies showed that, in rat models of SCI, inhibition of ER stress reverses the degeneration of TJ and AJ proteins and protects BSCB integrity[23, 25]. Whether inhibiting ER stress is protective for BSCB integrity in diabetes mellitus patients after SCI remains unclear. We first examined the effects of STZ-induced diabetes on BSCB disruption, ER stress, endothelial cell damage, and pericyte loss after SCI. The pathomechanism of SCI in diabetic rats is further verified in vitro via analysis in the co-stimulation of H2O2 and HG with and without 4-PBA

Methods

Results

Conclusion