scholarly journals Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniel J. Hellenbrand ◽  
Charles M. Quinn ◽  
Zachariah J. Piper ◽  
Carolyn N. Morehouse ◽  
Jordyn A. Fixel ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Immune Cell ◽  
Sensory Function ◽  
Glutamate Excitotoxicity ◽  
Secondary Injury ◽  
Extensive Literature ◽  
Secondary Damage ◽  
Cord Injury

AbstractTraumatic spinal cord injury (SCI) is a devastating neurological condition that results in a loss of motor and sensory function. Although extensive research to develop treatments for SCI has been performed, to date, none of these treatments have produced a meaningful amount of functional recovery after injury. The primary injury is caused by the initial trauma to the spinal cord and results in ischemia, oxidative damage, edema, and glutamate excitotoxicity. This process initiates a secondary injury cascade, which starts just a few hours post-injury and may continue for more than 6 months, leading to additional cell death and spinal cord damage. Inflammation after SCI is complex and driven by a diverse set of cells and signaling molecules. In this review, we utilize an extensive literature survey to develop the timeline of local immune cell and cytokine behavior after SCI in rodent models. We discuss the precise functional roles of several key cytokines and their effects on a variety of cell types involved in the secondary injury cascade. Furthermore, variations in the inflammatory response between rats and mice are highlighted. Since current SCI treatment options do not successfully initiate functional recovery or axonal regeneration, identifying the specific mechanisms attributed to secondary injury is critical. With a more thorough understanding of the complex SCI pathophysiology, effective therapeutic targets with realistic timelines for intervention may be established to successfully attenuate secondary damage.

scholarly journals CCL3 contributes to secondary damage after spinal cord injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Nicolas Pelisch ◽  
Jose Rosas Almanza ◽  
Kyle E. Stehlik ◽  
Brandy V. Aperi ◽  
Antje Kroner
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Lesion Size ◽  
Secondary Injury ◽  
Wild Type ◽  
Locomotor Recovery ◽  
Secondary Damage ◽  
Cord Injury

Abstract Background Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (macrophage inflammatory protein 1-α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system. Methods A mouse model of lower thoracic (T11) spinal cord contusion injury was used. We assessed expression levels of CCL3 and its receptors on the mRNA and protein level and analyzed changes in locomotor recovery and the inflammatory response in the injured spinal cord of wild-type and CCL3−/− mice. Results The expression of CCL3 and its receptors was increased after thoracic contusion SCI in mice. We then examined the role of CCL3 after SCI and its direct influence on the inflammatory response, locomotor recovery and lesion size using CCL3−/− mice. CCL3−/− mice showed mild but significant improvement of locomotor recovery, a smaller lesion size and reduced neuronal damage compared to wild-type controls. In addition, neutrophil numbers as well as the pro-inflammatory cytokines and chemokines, known to play a deleterious role after SCI, were markedly reduced in the absence of CCL3. Conclusion We have identified CCL3 as a potential target to modulate the inflammatory response and secondary damage after SCI. Collectively, this study shows that CCL3 contributes to progressive tissue damage and functional impairment during secondary injury after SCI.

Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury

2015 ◽  
Vol 44 ◽  
pp. 68-81 ◽  
Author(s):  
Yuriy Pomeshchik ◽  
Iurii Kidin ◽  
Paula Korhonen ◽  
Ekaterina Savchenko ◽  
Merja Jaronen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Secondary Injury ◽  
Interleukin 33 ◽  
Cord Injury

Blood glutamate scavengers and exercises as an effective neuroprotective treatment in mice with spinal cord injury

2020 ◽  
Vol 33 (5) ◽  
pp. 692-704
Author(s):  
Yona Goldshmit ◽  
Evgeni Banyas ◽  
Nicole Bens ◽  
Alex Yakovchuk ◽  
Angela Ruban
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Axonal Degeneration ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Glutamate Release ◽  
Combined Treatment ◽  
Secondary Damage ◽  
Cord Injury

OBJECTIVEExcitotoxicity due to neuronal damage and glutamate release is one of the first events that leads to the progression of neuronal degeneration and functional impairment. This study is based on a paradigm shift in the therapeutic approach for treating spinal cord injury (SCI). The authors tested a new treatment targeting removal of CNS glutamate into the blood circulation by injection of the blood glutamate scavengers (BGSs) recombinant enzyme glutamate-oxaloacetate transaminase (rGOT1) and its cosubstrate oxaloacetic acid (OxAc). Their primary objective was to investigate whether BGS treatment, followed by treadmill exercises in mice with SCI, could attenuate excitotoxicity, inflammation, scarring, and axonal degeneration and, at a later time point, improve functional recovery.METHODSA pharmacokinetic experiment was done in C57BL/6 naive mice to verify rGOT1/OxAc blood activity and to characterize the time curve of glutamate reduction in the blood up to 24 hours. The reduction of glutamate in CSF after BGS administration in mice with SCI was confirmed by high-performance liquid chromatography. Next, SCI (left hemisection) was induced in the mice, and the mice were randomly assigned to one of the following groups at 1 hour postinjury: control (underwent SCI and received PBS), treadmill exercises, rGOT1/OxAc treatment, or rGOT1/OxAc treatment followed by treadmill exercises. Treatment started 1 hour postinjury with an injection of rGOT1/OxAc and continued for 5 consecutive days. Starting 1 week after SCI, the exercises and the combined treatment groups recommenced the treadmill exercise regimen 5 days a week for 3 months. Locomotor function was assessed for 3 months using the horizontal grid walking test and CatWalk. Axonal anterograde and wallerian degenerations were evaluated using tetramethylrhodamine dextran. Tissue sections were immunofluorescently stained for Iba1, GFAP, GAP-43, synaptophysin, and NeuN.RESULTSBGS treatment decreased the CSF glutamate level up to 50%, reduced axonal wallerian degeneration, and increased axonal survival and GAP-43 expression in neuronal cells. Combined treatment reduced inflammation, scarring, and lesion size. Additionally, the combination of BGS treatment and exercises increased synapses around motor neurons and enhanced axonal regeneration through the lesion site. This resulted in motor function improvement 3 months post-SCI.CONCLUSIONSAs shown by biochemical, immunohistochemical, and functional analysis, BGSs exhibit a substantial neuroprotective effect by reducing excitotoxicity and secondary damage after SCI. Furthermore, in combination with exercises, they reduced axonal degeneration and scarring and resulted in improved functional recovery.

scholarly journals CCL3 contributes to secondary damage after spinal cord injury

2020 ◽  
Author(s):  
Nicolas Pelisch ◽  
Jose Rosas Almanza ◽  
Kyle Edward Stehlik ◽  
Brandy V Aperi ◽  
Antje Kroner
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Lesion Size ◽  
Secondary Injury ◽  
Wild Type ◽  
Locomotor Recovery ◽  
Secondary Damage ◽  
Cord Injury

Abstract Background: Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (Macrophage inflammatory protein 1- α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system. Methods: A mouse model of lower thoracic (T11) spinal cord contusion injury was used. We assessed expression levels of CCL3 and its receptors on the mRNA and protein level and analyzed changes in locomotor recovery and the inflammatory response in the injured spinal cord of wild-type and CCL3-/- mice.Results: The expression of CCL3 and its receptors is increased after thoracic contusion SCI in mice. We then examined the role of CCL3 after SCI and its direct influence on the inflammatory response, locomotor recovery and lesion size using CCL3 −/− mice. CCL3 −/− mice showed mild but significant improvement of locomotor recovery and a smaller lesion size compared to wild-type controls. In addition, neutrophil numbers as well as the pro-inflammatory cytokines and chemokines, known to play a deleterious role after SCI, were markedly reduced in the absence of CCL3 .Conclusion: We have identified CCL3 as a potential target to modulate the inflammatory response and secondary damage after SCI. Collectively, this study shows that the absence of CCL3 can contribute to reduced tissue damage and better functional recovery during secondary injury after SCI.

scholarly journals Inhibition of TGF-β repairs spinal cord injury by attenuating EphrinB2 expressing through inducing miR-484 from fibroblast

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dayu Pan ◽  
Fuhan Yang ◽  
Shibo Zhu ◽  
Yongjin Li ◽  
Guangzhi Ning ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Axon Growth ◽  
Neutralizing Antibody ◽  
Mapk Signaling ◽  
Sensory Function ◽  
Systemic Injection ◽  
Cord Injury ◽  
Fibrotic Scar

AbstractSpinal cord injury (SCI) can lead to severe loss of motor and sensory function with high disability and mortality. The effective treatment of SCI remains unknown. Here we find systemic injection of TGF-β neutralizing antibody induces the protection of axon growth, survival of neurons, and functional recovery, whereas erythropoietin-producing hepatoma interactor B2 (EphrinB2) expression and fibroblasts distribution are attenuated. Knockout of TGF-β type II receptor in fibroblasts can also decrease EphrinB2 expression and improve spinal cord injury recovery. Moreover, miR-488 was confirmed to be the most upregulated gene related to EphrinB2 releasing in fibroblasts after SCI and miR-488 initiates EphrinB2 expression and physical barrier building through MAPK signaling after SCI. Our study points toward elevated levels of active TGF-β as inducer and promoters of fibroblasts distribution, fibrotic scar formation, and EphrinB2 expression, and deletion of global TGF-β or the receptor of TGF-β in Col1α2 lineage fibroblasts significantly improve functional recovery after SCI, which suggest that TGF-β might be a therapeutic target in SCI.

The effect of glutamine on locomotor performance and skeletal muscle myosins following spinal cord injury in rats

2006 ◽  
Vol 101 (4) ◽  
pp. 1045-1052 ◽  
Author(s):  
Jamie D. Golding ◽  
Sarah T. Rigley MacDonald ◽  
Bernhard H. J. Juurlink ◽  
Benjamin W. C. Rosser
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Extensor Digitorum Longus ◽  
Critical Role ◽  
Extensor Digitorum ◽  
Secondary Injury ◽  
Significant Difference ◽  
Cord Injury ◽  
Functional Scores

Following initial spinal cord injury (SCI), a cascade of pathological events, including oxidative stress, leads to secondary injury. Glutathione (GSH) plays a critical role in oxidant scavenging. Maintenance of GSH concentrations after SCI lessens secondary injury and improves recovery. Since glutamine promotes GSH synthesis, this nonessential amino acid was examined for therapeutic potential. Denervation alters the expression of myosin heavy chain (MHC) isoforms within skeletal muscles. The hypotheses of this study were that glutamine administration to SCI rats would lead to improved functional recovery and more preserved MHC phenotypes in representative locomotor muscles. Male Wistar rats were divided into four groups: healthy, sham with laminectomy, laminectomized SCI untreated, and laminectomized SCI treated with glutamine. Functional performance was measured weekly for 6 wk using Basso-Beattie-Bresnahan scale and angle board methods. MHC composition of rat soleus and extensor digitorum longus muscles was determined using SDS-PAGE. Glutamine-treated rats had significantly higher angle board scores ( P < 0.001) and Basso-Beattie-Bresnahan scores ( P < 0.01) than untreated SCI rats. Soleus of healthy rats contained 94% type 1 myosin isoform. Treated rats maintained 68%, which was significantly ( P < 0.001) greater than 28% in untreated rats. The extensor digitorum longus of healthy rats contained 55% type 2b myosin. There was a significant ( P < 0.001) decrease in this isoform following SCI, but no significant difference between treated and untreated groups. There were strong correlations between higher functional scores and more preserved MHC phenotypes. Our findings suggest glutamine improves functional recovery and helps preserve myosin profile by reducing secondary SCI, thereby maintaining more nerves.

Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury

2020 ◽  
Author(s):  
Yao Li ◽  
Jing Zhang ◽  
Kailiang Zhou ◽  
Ling Xie ◽  
Guangheng Xiang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Functional Recovery ◽  
Sensory Function ◽  
Autophagic Flux ◽  
Critical Determinant ◽  
Cord Injury

Abstract Background Spinal cord injury (SCI) is a devastating central neurological trauma that causes a loss of motor and sensory function. Sestrin2, also known as hypoxia inducible gene 95 (Hi95), is emerging as a critical determinant of cell homeostasis in response to cellular stress. However, the role of sestrin2 in neuron response to endoplasmic reticulum (ER) stress and potential mechanism remains undefined. In this study, we investigated the effects of sestrin2 on ER stress and delineated a underlying molecular mechanism after SCI. Methods The induction of sestrin2 after traumatic injury and ER stress insult were investigated in vitro and in vivo. West blot and immunofluorescence were used to analyze the potential mechanisms of sestrin2 on autophagy and ER stress after SCI. Behavior assessment were used to evaluated the effect of sestrin2 on function recovery in vivo. Results Elevated sestrin2 is a protective process in neurons against chemical ER stress induced by tunicamycin (TM) or traumatic invasion. While treatment with PERK inhibitor or knockdown of ATF4 reduces sestrin2 expression upon ER stress. In addition, overexpression of sestrin2 limits ER stress, promotes the survival of neuron and improves functional recovery after SCI, which is associated with activation of autophagy and restoration of autophagic flux mediated by sestrin2. Meanwhile, sestrin2 activates autophagy dependent on AMPK-mTOR signaling pathway. Consistently, inhibition of AMPK abrogates the effect of sestrin2 on activation of autophagy, and blockage of autophagic flux abolishes the effect of sestrin2 on limiting ER stress and neural death. Conclusion Upregulation of sestrin2 as an important resistance mechanism of neuron to ER stress, and its potential role as a therapeutic target for SCI.

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