Abstract
BackgroundThe permeability of the blood-spinal cord barrier (BSCB) is mainly determined by junction complexes between adjacent endothelial cells (ECs), including tight junctions (TJs) and adherens junctions (AJs), which can be severely damaged after spinal cord injury (SCI). Exercise training is a recognized method for the treatment of SCI. The destruction of the BSCB mediated by matrix metalloproteinases (MMPs) leads to inflammation, neurotoxin production, and neuronal apoptosis. The failure of new blood vessels to effectively regenerate is also an important cause of delayed recovery after SCI. For the first time, we introduced water treadmill training (TT) to help SCI rats successfully exercise and measured the effects of TT in promoting recovery after SCI and the possible mechanisms involved.MethodsSprague-Dawley (200–250 g) rats were randomly divided into the following three groups: sham operated, SCI, and SCI + TT. Animals were sacrificed at 7 or 14 days post-surgery. The degree of neurological deficit, tissue morphology and BSCB permeability were assessed by the Basso-Beattie-Bresnahan (BBB) motor function scale and appropriate staining protocols, and apoptosis, protein expression and vascular EC ultrastructure were assessed by TUNEL staining, Western blotting, immunofluorescence and transmission electron microscopy (TEM).ResultsOur experiments showed that TT reduced permeability of the BSCB and decreased structural tissue damage. TT significantly improved functional recovery when compared with that in the SCI group; TJ and AJ proteins expression increased significantly after TT, and training reduced apoptosis induced by SCI. TT could promote angiogenesis, and MMP-2 and MMP-9 expression was significantly inhibited by TT.ConclusionsThe results of this study indicate that TT promotes functional recovery for the following reasons: TT (1) protects residual BSCB structure from further damage, (2) promotes vascular regeneration, and (3) inhibits MMP-2/9 expression to mitigate BSCB damage.
Highlights
The permeability of the blood-spinal cord barrier (BSCB) is mainly determined by junction complexes between adjacent endothelial cells (ECs), including tight junctions (TJs) and adherens junctions (AJs), which can be severely damaged after spinal cord injury (SCI)
The results showed that the water content increased significantly after SCI and that treadmill training (TT) could reduce the oedema caused by SCI at both 7 and 14 d after SCI (Fig. 1b, e) (M vs. S: p7 < 0.001, p14 < 0.001; TM vs. M: p7 < 0.01, p14 < 0.001)
Staining for Occludin/Platelet endothelial cell adhesion molecule-1 (CD31)/Hoechst (Fig. 3c), Claudin-5/CD31/Hoechst (Fig. 3d), p120-Catenin/CD31/ Hoechst (Fig. 4a) and β-Catenin/CD31/Hoechst (Fig. 4b) was used to show the distribution of BSCB proteins after SCI and indicated that TT reduced the degradation of Claudin-5/Occludin/p120-Catenin/β-Catenin around the epicentre. These results suggest that TT could prevent the loss of TJ and AJ proteins after SCI
Summary
The permeability of the blood-spinal cord barrier (BSCB) is mainly determined by junction complexes between adjacent endothelial cells (ECs), including tight junctions (TJs) and adherens junctions (AJs), which can be severely damaged after spinal cord injury (SCI). After SCI, barrier integrity is compromised by the disruption of interendothelial tight junctions (TJs) and adherens junctions (AJs) as well as overall mechanical damage to vessels. This compromise in the BSCB results in the infiltration of immune cells and neurotoxic products, causing the death of nerve cells, and permanent neurological dysfunction [5,6,7]. There is a crucial need to identify interventions that can effectively prevent BSCB destruction after SCI
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