Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury

Gonzalez, Rafael; Glaser, Janette; Liu, Michael T.; Lane, Thomas E.; Keirstead, Hans S.

doi:10.1016/s0014-4886(03)00257-7

Cited by 146 publications

(122 citation statements)

References 37 publications

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“…Following spinal cord injury (SCI), a cascade of pathological processes occurs, including the breaking down of the vasculature system, edema, infiltration of immune cells, inflammation, initiation of wound healing processes, seizing of ongoing neurotransmission, gliosis/glial scar formation, cell death, demyelination, and remyelination (7), along with activation of neural stem/ progenitor cells (NPCs) attempting to participate in neural repair (8). Often, prolonged activation of immune cells, including microglia, lymphocytes, and macrophages, leads to secondary lesions of the nervous system, creating a very harsh environment for already compromised CNS neurons to regenerate axons (9).…”

mentioning

confidence: 99%

NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

Yang

Zhang

Duan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

177

172

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Neural stem cells (NSCs) in the adult mammalian central nervous system (CNS) hold the key to neural regeneration through proper activation, differentiation, and maturation, to establish nascent neural networks, which can be integrated into damaged neural circuits to repair function. However, the CNS injury microenvironment is often inhibitory and inflammatory, limiting the ability of activated NSCs to differentiate into neurons and form nascent circuits. Here we report that neurotrophin-3 (NT3)-coupled chitosan biomaterial, when inserted into a 5-mm gap of completely transected and excised rat thoracic spinal cord, elicited robust activation of endogenous NSCs in the injured spinal cord. Through slow release of NT3, the biomaterial attracted NSCs to migrate into the lesion area, differentiate into neurons, and form functional neural networks, which interconnected severed ascending and descending axons, resulting in sensory and motor behavioral recovery. Our study suggests that enhancing endogenous neurogenesis could be a novel strategy for treatment of spinal cord injury.spinal cord injury | NT3 | chitosan | functional recovery | endogenous neurogenesis

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mentioning

confidence: 99%

NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

Yang

Zhang

Duan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

177

172

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“…2,3,8 The current paper continues this theme and demonstrates that acute treatment with Reparixin, a small molecule antagonist that inhibits CXCR1 and CXCR2 chemokine receptors, improves motor and autonomic neurological outcomes after SCI. The 72-h Reparixin treatment diminished SCI-induced expression of cytokine TNF-a, chemokine CINC-1 and reduced inflammation in the spinal cord lesion.…”

Section: Discussionmentioning

confidence: 73%

“…1 Recently, treatment strategies designed to selectively reduce inflammation and cell death after SCI have demonstrated increased axonal sparing, neuroprotection and improved neurological outcomes after SCI. [2][3][4][5][6] Targets have included chemokine receptors, 3,4,7 cell adhesion integrins, 2,8 and cytokines and death receptors 5,6 that are upregulated after SCI.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury

Marsh

Flemming

2010

Spinal Cord

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Study design: Female Wistar rats (225 g) underwent spinal cord injury (SCI) at the T4 segment and were assigned to one of the three groups treated with: (1) saline; (2) 7.5 mg kg -1 Reparixin; or (3) 15 mg kg -1 Reparixin. Reparixin is a small molecule, allosteric noncompetitive inhibitor of CXCR1 and CXCR2 chemokine receptors involved in inflammation. Methods: Spinal cord homogenates at 12 and 72 h post-SCI were assayed for tumor necrosis factor a (TNF-a) and cytokine-induced neutrophil chemoattractant (CINC)-1 using enzyme-linked immunosorbant assay (ELISA). Myeloperoxidase activity and western blots for CD68, Fas and p75 content were used to assess inflammation and death receptor ligands, respectively. Histopathology and neurological outcomes were assessed by immunohistochemistry, locomotion scoring and cardiovascular measurement of autonomic dysreflexia 4 weeks post-SCI. Results: Both 7.5 and 15 mg kg -1 doses of Reparixin reduced levels of TNF-a and CINC-1 72 h post-SCI and decreased macrophage (CD68) content in the spinal cord lesion. Only 15 mg kg -1 Reparixin reduced both Fas and p75 levels in the spinal cord compared with untreated SCI. We observed a reduced lesion area and increased neuron number in the gray matter of Reparixin-treated rats. Hindlimb motor scores at 7 and 28 days post-SCI were improved by 15 mg kg -1 Reparixin treatment. Both 7.5 and 15 mg kg -1 Reparixin reduced development of autonomic dysreflexia 4 weeks post-SCI. The change in mean arterial pressure, induced by cutaneous or visceral stimulation, was reduced by 40-50%. Conclusion: Acute treatment with 15 mg kg -1 Reparixin reduces acute inflammation and is associated with minor improvements in motor function and a significant reduction in the severity of autonomic dysreflexia.

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“…The neutralization reduced apoptosis,122 inhibited T‐lymphocyte invasion124 and inflammation,125 and thus enhanced tissue sparing 123. CXCL10 neutralization also enhanced angiogenesis and the subsequent axon sprouting.…”

Section: Roles Of Inflammatory Cytokines In Sci Repairmentioning

confidence: 97%

“…Gonzalez et al first showed that antibody neutralization of CXCL10 enhanced functional recovery in a mouse dorsal hemisection SCI model 124. The neutralization reduced apoptosis,122 inhibited T‐lymphocyte invasion124 and inflammation,125 and thus enhanced tissue sparing 123.…”

Section: Roles Of Inflammatory Cytokines In Sci Repairmentioning

confidence: 99%

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

et al. 2018

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The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI.

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Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury

Cited by 146 publications

References 37 publications

NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

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