Matrix Metalloproteinase-8 Inhibition Prevents Disruption of Blood–Spinal Cord Barrier and Attenuates Inflammation in Rat Model of Spinal Cord Injury

Abstract Background: The permeability of blood-spinal cord barrier (BSCB) is mainly determined by the junction complex between adjacent endothelial cells, including tight junctions (TJ) and adhesion junctions (AJ), 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 metalloproteinase (MMP) leads to inflammation, neurotoxin production, and apoptosis of neurons. The failure of effective regeneration of new blood vessels is also an important reason for delayed recovery after SCI. We introduced water treadmill training (TT) for the first time, which can help SCI rats successfully exercise and measured the effect of TT in promoting recovery after SCI and possible mechanisms involved.Methods: Sprague-Dawley (200–250g) rats were randomly divided into three groups: Sham operated, SCI, and SCI + TT. Animals were sacrificed 7 d or 14 d post-surgery. The degree of neurological deficit as assessed by the Basso-Beattie-Bresnahan motor rating scale, tissue water content, BSCB permeability, apoptosis, protein expression and ultrastructure of vascular endothelial cells were assessed, Western blot, immunofluorescence and transmission electron microscopy. Results: Our experiments showed that TT reduced the permeability of BSCB and decreased tissue structural damage. TT improved functional recovery significantly when compared with the SCI group; TJ and AJ proteins expression increased significantly after TT training and training reduced apoptosis induced by SCI. TT can promote angiogenesis and the expression of MMP-2 and MMP-9 was significantly inhibited by TT.Conclusions: In this study, the results indicate that TT promotes functional recovery for the following reasons: (1) TT protects residual BSCB structure from further damage; (2) it promotes vascular regeneration; and (3) it inhibits the expression of MMP-2/9 to mitigate BSCB damage.

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Matrix Metalloproteinase-3 Promotes Early Blood–Spinal Cord Barrier Disruption and Hemorrhage and Impairs Long-Term Neurological Recovery after Spinal Cord Injury

American Journal Of Pathology ◽

10.1016/j.ajpath.2014.07.016 ◽

2014 ◽

Vol 184 (11) ◽

pp. 2985-3000 ◽

Cited By ~ 40

Author(s):

Jee Youn Lee ◽

Hae Young Choi ◽

Hyun-Jong Ahn ◽

Bong Gun Ju ◽

Tae Young Yune

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Matrix Metalloproteinase ◽

Neurological Recovery ◽

Matrix Metalloproteinase 3 ◽

Barrier Disruption ◽

Cord Injury ◽

Blood Spinal Cord Barrier

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Decreased angiogenesis as a possible pathomechanism in cervical degenerative myelopathy

Scientific Reports ◽

10.1038/s41598-021-81766-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Christian Blume ◽

M. F. Geiger ◽

M. Müller ◽

H. Clusmann ◽

V. Mainz ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neurological Status ◽

Consecutive Series ◽

Inflammatory Reactions ◽

Immune Mediated ◽

Elisa Testing ◽

Cord Injury ◽

Blood Spinal Cord Barrier ◽

Angiopoietin 2

AbstractEndogenous immune mediated reactions of inflammation and angiogenesis are components of the spinal cord injury in patients with degenerative cervical myelopathy (DCM). The aim of this study was to identify alteration of certain mediators participating in angiogenetic and inflammatory reactions in patients with DCM. A consecutive series of 42 patients with DCM and indication for surgical decompression were enrolled for the study. 28 DCM patients were included, as CSF samples were taken preoperatively. We enrolled 42 patients requiring surgery for a thoracic abdominal aortic aneurysm (TAAA) as neurologically healthy controls. In 38 TAAA patients, CSF samples were taken prior to surgery and thus included. We evaluated the neurological status of patients and controls prior to surgery including NDI and mJOA. Protein-concentrations of factors with a crucial role in inflammation and angiogenesis were measured in CSF via ELISA testing (pg/ml): Angiopoietin 2, VEGF-A and C, RANTES, IL 1 beta and IL 8. Additionally, evaluated the status of the blood-spinal cord barrier (BSCB) by Reibers´diagnostic in all participants. Groups evidently differed in their neurological status (mJOA: DCM 10.1 ± 3.3, TAAA 17.3 ± 1.2, p < .001; NDI: DCM 47.4 ± 19.7, TAAA 5.3 ± 8.6, p < .001). There were no particular differences in age and gender distribution. However, we detected statistically significant differences in concentrations of mediators between the groups: Angiopoietin 2 (DCM 267.1.4 ± 81.9, TAAA 408.6 ± 177.1, p < .001) and VEGF C (DCM 152.2 ± 96.1, TAAA 222.4 ± 140.3, p = .04). DCM patients presented a mild to moderate BSCB disruption, controls had no signs of impairment. In patients with DCM, we measured decreased concentrations of angiogenic mediators. These results correspond to findings of immune mediated secondary harm in acute spinal cord injury. Reduced angiogenic activity could be a relevant part of the pathogenesis of DCM and secondary harm to the spinal cord.

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Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury

Nature Communications ◽

10.1038/s41467-021-22137-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marco Bonizzato ◽

Nicholas D. James ◽

Galyna Pidpruzhnykova ◽

Natalia Pavlova ◽

Polina Shkorbatova ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Stress Responses ◽

Learning Algorithm ◽

Lumbar Spinal Cord ◽

Cord Injury ◽

Potential Synergy ◽

Lumbar Spinal ◽

Deep Brain

AbstractA spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions.

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A Collagen-Based Scaffold for Promoting Neural Plasticity in a Rat Model of Spinal Cord Injury

Polymers ◽

10.3390/polym12102245 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2245

Author(s):

Jue-Zong Yeh ◽

Ding-Han Wang ◽

Juin-Hong Cherng ◽

Yi-Wen Wang ◽

Gang-Yi Fan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Neural Plasticity ◽

Collagen Scaffold ◽

Glial Scar ◽

Beneficial Effects ◽

Cord Injury

In spinal cord injury (SCI) therapy, glial scarring formed by activated astrocytes is a primary problem that needs to be solved to enhance axonal regeneration. In this study, we developed and used a collagen scaffold for glial scar replacement to create an appropriate environment in an SCI rat model and determined whether neural plasticity can be manipulated using this approach. We used four experimental groups, as follows: SCI-collagen scaffold, SCI control, normal spinal cord-collagen scaffold, and normal control. The collagen scaffold showed excellent in vitro and in vivo biocompatibility. Immunofluorescence staining revealed increased expression of neurofilament and fibronectin and reduced expression of glial fibrillary acidic protein and anti-chondroitin sulfate in the collagen scaffold-treated SCI rats at 1 and 4 weeks post-implantation compared with that in untreated SCI control. This indicates that the collagen scaffold implantation promoted neuronal survival and axonal growth within the injured site and prevented glial scar formation by controlling astrocyte production for their normal functioning. Our study highlights the feasibility of using the collagen scaffold in SCI repair. The collagen scaffold was found to exert beneficial effects on neuronal activity and may help in manipulating synaptic plasticity, implying its great potential for clinical application in SCI.

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Does Neuroectodermal Stem Cells Transplantation Restore Neural Regeneration and Locomotor Functions in Compressed Spinal Cord Injury Rat Model?

International Journal of Morphology ◽

10.4067/s0717-95022019000100349 ◽

2019 ◽

Vol 37 (1) ◽

pp. 349-357

Author(s):

Saleh Al-Karim ◽

Wafaa S Ramadan ◽

Ghada A Abdel-Hamid ◽

Fatma Al-Qudsi

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Rat Model ◽

Neural Regeneration ◽

Cord Injury ◽

Stem Cells Transplantation

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The Therapeutic Potential of Conditioned Medium from Human Breast Milk Stem Cells in Treating Spinal Cord Injury

Asian Spine Journal ◽

10.31616/asj.2019.0026 ◽

2020 ◽

Vol 14 (2) ◽

pp. 131-138 ◽

Cited By ~ 1

Author(s):

Maryam Borhani-Haghighi ◽

Shadan Navid ◽

Yousef Mohamadi

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Breast Milk ◽

Conditioned Medium ◽

Rat Model ◽

Intrathecal Administration ◽

Human Breast Milk ◽

Human Breast ◽

Cord Injury

Study Design: Experimental animal study.Purpose: This study investigated the therapeutic effects of human breast milk stem cell (BMSC)-conditioned medium (BMSC-CM) in a model of spinal cord injury (SCI) in male Sprague-Dawley rats.Overview of Literature: SCI is one of the leading causes of disability in addition to sensory and motor impairment. So far, there have been no successful treatments for SCI. Given the positive outcomes associated with using stem cells and their derivatives as a treatment for various diseases, there is a growing interest in using them as an SCI treatment. Recent research has demonstrated that CM from stem cells has therapeutic advantages.Methods: Human BMSCs were isolated and characterized, and CM was subsequently collected. Animals received an intrathecal administration of BMSC-CM after SCI. The activity of caspase-3 was measured to assess apoptosis, and levels of tumor necrosis factor-α and interleukin-1β were measured to assess inflammation. Also, sensory and locomotor performances were assessed after SCI and BMSC-CM administration.Results: Administration of CM from BMSC reduced apoptosis and inflammation at the site of injury in a rat model of SCI (p<0.05). Motor, sensory, locomotor, and sensorimotor performances were significantly improved in rats that received BMSC-CM after SCI.Conclusions: Intrathecal administration of BMSC-CM improved recovery in a rat model of SCI.

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