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Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses.

ABSTRACT: Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes.

SUBMITTER: Orr MB

PROVIDER: S-EPMC6095779 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses.

Orr Michael B MB Gensel John C JC

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20180701 3

Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focus ...[more]

PMID: 29717413

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Project description:The purpose of the present study was to examine the efficacy of targeting inflammation as a means of improving mood following spinal cord injury (SCI) and explore the potential mechanisms of action.The study was a randomized, parallel-group, controlled, clinical trial (NCT02099890) whereby 20 participants with varying levels and severities of SCI were randomized (3:2) to either the treatment group, consisting of a 12-week anti-inflammatory diet, or control group. Outcome measures were assessed at baseline, 1 and 3 months, and consisted of CES-D scores of depression, markers of inflammation as assessed by various pro- and anti-inflammatory cytokines and several amino acids related to depression.A significant group × time interaction was found for CES-D (Center for Epidemiologic studies Depression Scale) score (p?=?0.01), the TRP/LNAA (tryptophan/large neutral amino acid) ratio (p?=?0.04), the composite score of pro-inflammatory cytokines (p?=?0.04), IL-1? (interleukin-1 beta) (p?=?0.04), and IFN-? (interferon gamma) (p?=?0.03). Pearson's r correlation showed significance between the ?IL-1? and both the ?CES-D score (r?=?0.740, p?<?0.01) and the ?KYN/TRP (kynurenine/tryptophan) ratio (r?=?0.536, p?=?0.02). The ?KYN/TRP ratio was also significantly correlated with the ?CES-D score (r?=?0.586, p?=?0.01). Mediation analysis showed that the relationship between the ?KYN/TRP ratio and the ?CES-D score was mediated by the ?IL-1?. Subgroup analysis showed that participants with high CES-D scores had significantly higher concentrations of IL-1?, and all correlations were maintained or strengthened within this subgroup.Overall, the results demonstrated the effectiveness of targeting inflammation as a means of improving mood in SCI, with potential mechanisms relating to the reduction in IL-1? and improvements in levels of neuroactive compounds related to the kynurenine pathway. Due to the limited sample size, results should be interpreted with caution; however, they are worthy of further examination due to the potential impact of inflammation on depression.ClinicalTrials.gov ID: NCT02099890 .

Dataset Information

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses.

Publications

Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses.

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