Dataset Information

IVIg attenuates complement and improves spinal cord injury outcomes in mice.

ABSTRACT:

Objective

Traumatic spinal cord injury (SCI) elicits immediate neural cell death, axonal damage, and disruption of the blood-spinal cord barrier, allowing circulating immune cells and blood proteins into the spinal parenchyma. The inflammatory response to SCI involves robust complement system activation, which contributes to secondary injury and impairs neurological recovery. This study aimed to determine whether intravenous immunoglobulin (IVIg), an FDA-approved treatment for inflammatory conditions, can scavenge complement activation products and improve recovery from contusive SCI.

Methods

We used functional testing, noninvasive imaging, and detailed postmortem analysis to assess whether IVIg therapy is effective in a mouse model of severe contusive SCI.

Results

IVIg therapy at doses of 0.5-2 g/kg improved the functional and histopathological outcomes from SCI, conferring protection against lesion enlargement, demyelination, central canal dilation, and axonal degeneration. The benefits of IVIg were detectable through noninvasive diffusion tensor imaging (DTI), with IVIg treatment counteracting the progressive SCI-induced increase in radial diffusivity (RD) in white matter. Diffusion indices significantly correlated with the functional performance of individual mice and accurately predicted the degree of myelin preservation. Further experiments revealed that IVIg therapy reduced the presence of complement activation products and phagocytically active macrophages at the lesion site, providing insight as to its mechanisms of action.

Interpretation

Our findings highlight the potential of using IVIg as an immunomodulatory treatment for SCI, and the value of DTI to assess tissue damage and screen for the efficacy of candidate intervention strategies in preclinical models of SCI, both quantitatively and noninvasively.

SUBMITTER: Brennan FH

PROVIDER: S-EPMC4931715 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

IVIg attenuates complement and improves spinal cord injury outcomes in mice.

Brennan Faith H FH Kurniawan Nyoman D ND Vukovic Jana J Bartlett Perry F PF Käsermann Fabian F Arumugam Thiruma V TV Basta Milan M Ruitenberg Marc J MJ

Annals of clinical and translational neurology 20160525 7

<h4>Objective</h4>Traumatic spinal cord injury (SCI) elicits immediate neural cell death, axonal damage, and disruption of the blood-spinal cord barrier, allowing circulating immune cells and blood proteins into the spinal parenchyma. The inflammatory response to SCI involves robust complement system activation, which contributes to secondary injury and impairs neurological recovery. This study aimed to determine whether intravenous immunoglobulin (IVIg), an FDA-approved treatment for inflammato ...[more]

PMID: 27386499

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Project description:Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system. Therefore, early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury. Bexarotene, a type of retinoid, exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease. Bexarotene has been proven to promote autophagy, but it has not been used in the treatment of spinal cord injury. To investigate the effects of bexarotene on spinal cord injury, we established a mouse model of T11-T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days. We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord, increased the number of synapses of nerve cells, reduced oxidative stress, inhibited pyroptosis, promoted the recovery of motor function, and reduced death. Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury. Bexarotene enhanced the nuclear translocation of transcription factor E3, which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways. Intravenous injection of transcription factor E3 shRNA or intraperitoneal injection of compound C, an AMP-activated protein kinase blocker, inhibited the effects of bexarotene. These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways, promotes autophagy, decreases reactive oxygen species level, inhibits pyroptosis, and improves motor function after spinal cord injury.

Dataset Information

IVIg attenuates complement and improves spinal cord injury outcomes in mice.

Objective

Methods

Results

Interpretation

Publications

IVIg attenuates complement and improves spinal cord injury outcomes in mice.

Similar Datasets

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