Abstract
Spinal cord injury induces the disruption of blood-spinal cord barrier and triggers a complex array of tissue responses, including endoplasmic reticulum (ER) stress and autophagy. However, the roles of ER stress and autophagy in blood-spinal cord barrier disruption have not been discussed in acute spinal cord trauma. In the present study, we respectively detected the roles of ER stress and autophagy in blood-spinal cord barrier disruption after spinal cord injury. Besides, we also detected the cross-talking between autophagy and ER stress both in vivo and in vitro. ER stress inhibitor, 4-phenylbutyric acid, and autophagy inhibitor, chloroquine, were respectively or combinedly administrated in the model of acute spinal cord injury rats. At day 1 after spinal cord injury, blood-spinal cord barrier was disrupted and activation of ER stress and autophagy were involved in the rat model of trauma. Inhibition of ER stress by treating with 4-phenylbutyric acid decreased blood-spinal cord barrier permeability, prevented the loss of tight junction (TJ) proteins and reduced autophagy activation after spinal cord injury. On the contrary, inhibition of autophagy by treating with chloroquine exacerbated blood-spinal cord barrier permeability, promoted the loss of TJ proteins and enhanced ER stress after spinal cord injury. When 4-phenylbutyric acid and chloroquine were combinedly administrated in spinal cord injury rats, chloroquine abolished the blood-spinal cord barrier protective effect of 4-phenylbutyric acid by exacerbating ER stress after spinal cord injury, indicating that the cross-talking between autophagy and ER stress may play a central role on blood-spinal cord barrier integrity in acute spinal cord injury. The present study illustrates that ER stress induced by spinal cord injury plays a detrimental role on blood-spinal cord barrier integrity, on the contrary, autophagy induced by spinal cord injury plays a furthersome role in blood-spinal cord barrier integrity in acute spinal cord injury.
Highlights
The blood-spinal cord barrier (BSCB) is a highly specialized endothelial structure of the fully differentiated neurovascular system between the blood circulation and neural tissue features unique characteristics, which plays an important role in the highly precise control of the microenvironment [1,2,3]
When 4-phenylbutyric acid and chloroquine were combinedly administrated in spinal cord injury rats, chloroquine abolished the blood-spinal cord barrier protective effect of 4-phenylbutyric acid by exacerbating endoplasmic reticulum (ER) stress after spinal cord injury, indicating that the cross-talking between autophagy and ER stress may play a central role on blood-spinal cord barrier integrity in acute spinal cord injury
It is well known that the expression levels and distribution of tight junction (TJ) and adherens junctions (AJ) proteins are closely related to BSCB integrity [37]
Summary
The blood-spinal cord barrier (BSCB) is a highly specialized endothelial structure of the fully differentiated neurovascular system between the blood circulation and neural tissue features unique characteristics, which plays an important role in the highly precise control of the microenvironment [1,2,3]. ER stress is involved in regulation of a series of cell processes, including autophagy [14,15,16], apoptosis and the complicated regulatory network of them. Recent literatures indicate that GRP78 and PERK/eIF2a are involved in autophagy activation in neural cells [14], and autophagy formation is a cellular defense mechanism against ER stress-mediated apoptosis. Perior research has reported that the expression of Occludin and Claudin-1 were significantly increased by ER stress inducer thapsigargin (TG) that treated retinal pigment epithelial cells in vitro [18, 19]. The relationship between ER stress and BSCB integrity still need to be well described or studied
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