Adenovirus-delivered GFP-HO-1C[INCREMENT]23 attenuates blood–spinal cord barrier permeability after rat spinal cord contusion

Abstract

The blood-spinal cord barrier (BSCB) plays a key role in maintaining the microenvironment and is primarily composed of tight junction proteins and nonfenestrated capillary endothelial cells. After injury, BSCB damage results in increasing capillary permeability and release of inflammatory factors. Recent studies have reported that haem oxygenase-1 (HO-1) fragments lacking 23 amino acids at the C-terminus (HO-1C[INCREMENT]23) exert novel anti-inflammatory and antioxidative effects in vitro. However, no study has identified the role of HO-1C[INCREMENT]23 in vivo. We aimed to investigate the protective effects of HO-1C[INCREMENT]23 on the BSCB after spinal cord injury (SCI) in a rat model. Here, adenoviral HO-1C[INCREMENT]23 (Ad-GFP-HO-1C[INCREMENT]23) was intrathecally injected into the 10th thoracic spinal cord segment (T10) 7 days before SCI. In addition, nuclear and cytoplasmic extraction and immunofluorescence staining of HO-1 were used to examine the effect of Ad-GFP-HO-1C[INCREMENT]23 on HO-1 nuclear translocation. Evan's blue staining served as an index of capillary permeability and was detected by fluorescence microscopy at 633 nm. Western blotting was also performed to detect tight junction protein expression. The Basso, Beattie and Bresnahan score was used to evaluate kinematic functional recovery through the 28th day after SCI. In this study, the Ad-GFP-HO-1C[INCREMENT]23 group showed better kinematic functional recovery after SCI than the Ad-GFP and Vehicle groups, as well as smaller reductions in TJ proteins and capillary permeability compared with those in the Ad-GFP and Vehicle groups. These findings indicated that Ad-GFP-HO-1C[INCREMENT]23 might have a potential therapeutic effect that is mediated by its protection of BSCB integrity.

Experimental treatments to attenuate blood spinal cord barrier rupture in rats with traumatic spinal cord injury: A meta-analysis and systematic review

“…Further, four studies also confirmed the effect of inhibiting the Akt pathway on BSCB ( Table 1 ). Chang et al (2018) demonstrated that GFP-HO-1CΔ23 enhances HO-1 activity to protect BSCB. Wang et al (2017) also showed that A Thermosensitive Heparin-Poloxamer Hydrogel Bridges aFGF (aFGF-HP) hydrogels inhibit ER stress to alleviate BSCB rupture.…”

“…The forest plot showed that Xin et al (2021) had the greatest reduction (90%) in EB leakage, treated with BMSC-Exos. Further, Joshi et al (2020) treated with CORM-2-SLN (74%), Chang et al (2018) treated with GFP-HO-1CΔ23 (76%), Park et al (2022) treated with carvacrol (80%), and Park et al (2019) treated with Protocatechuic acid (78%). These studies all achieved >70% reduction in EB leakage.…”

“…Moreover, infiltration of inflammatory cells and increased expression of MMPs exacerbate the destruction of BSCB ( Zhang et al, 2011 ). Although the exact mechanism associated with BSCB disruption is currently unknown, it is closely related to MMPs, ER stress, and the Akt pathway ( Zhou et al, 2016a ; Chang et al, 2018 ; Chang and Cao, 2021 ; Xin et al, 2021 ). Regulation of related proteins can significantly reduce EB leakage and increase TJ protein expression ( Xin et al, 2021 ).…”

“…This finding Frontiers in Pharmacology frontiersin.org suggests that reducing the damage of BSCB can significantly improve motor function. Among them, the BBB score in Wang et al (2017) and Chang et al (2018) increased by 10 points. This indicates that the two treatments, GFP-HO-1CΔ23 and aFGF-HP hydrogels, are very effective at promoting functional recovery.…”

Sulfasalazine maintains blood–brain barrier integrity and relieves lipopolysaccharide-induced inflammation in hCMEC/D3 cells

“…In our previous research, we found that adenovirus-mediated delivery of HO-1C∆23 preserves blood-spinal cord barrier integrity in vivo [45]. However, we focused on the ability of certain drugs to pass through barriers [46] and neglected the interaction of inflammatory factors with the BBB.…”