Abstract
BackgroundEvidence suggests that the inflammatory events in the acute phase of spinal cord injury (SCI) exacerbate the initial trauma to the cord leading to poor functional recovery. As a result, minimizing the detrimental aspects of the inflammatory response after SCI is a promising treatment strategy. In this regard, immunoglobulin G (IgG) from pooled human serum is a promising treatment candidate. Due to its putative, though poorly characterized immuno-modulatory effects, IgG has been used clinically to treat neuroinflammatory disorders such as Guillain-Barré syndrome, but its effects in neurotrauma remain largely unexplored.MethodsThis study examines the potential neuroprotective effects of IgG in a well-characterized cervical model of SCI. Female Wistar rats were subject to moderate-severe clip compression injury at the C7-T1 level. IgG (0.4 g/kg) or saline was injected intravenously to randomly selected animals at 15 min post SCI. At several time points post SCI, biochemical assays, histology and immunohistochemistry analyses, and neurobehavioral assessments were used to examine the neuroprotective effects of IgG at the molecular, cellular, and neurobehavioral levels.ResultsWe found that intravenous treatment of IgG following acute clip-compression SCI at C7-T1 significantly reduced two important inflammatory cytokines: interleukin (IL)-1β and IL-6. This early reduction in pro-inflammatory signaling was associated with significant reductions in neutrophils in the spinal cord and reductions in the expression of myeloperoxidase and matrix metalloproteinase-9 in the injured spinal cord at 24 h after SCI. These beneficial effects of IgG were associated with enhanced tissue preservation, improved neurobehavioral recovery as measured by the BBB and inclined plane tests, and enhanced electrophysiological evidence of central axonal conduction as determined by motor-evoked potentials.ConclusionThe findings from this study indicate that IgG is a novel immuno-modulatory therapy which shows promise as a potential treatment for SCI.
Highlights
Spinal cord injury (SCI) consists of two defined injury processes termed the ‘primary’ and ‘secondary’ injury [13]
We provide novel evidence that immunoglobulin G (IgG) attenuates post-injury rises in interleukin (IL)-1β and IL-6, reduces the extent of neutrophil invasion and post-traumatic levels of matrix metalloproteinases (MMPs)-9 and myeloperoxidase, is associated with perilesional tissue sparing, and promotes neurobehavioral and electrophysiological evidence of functional recovery
Non-injured animals with IgG injection contained no parenchymal IgG (Figure 1B, right panel). This suggests that spinal cord injury (SCI) enabled IgG to cross the blood-spinal cord barrier (BSCB)
Summary
Spinal cord injury (SCI) consists of two defined injury processes termed the ‘primary’ and ‘secondary’ injury [13]. The secondary injury involves a cascade of cellular and molecular events that leads to the destruction of spinal tissue integrity beyond the site of injury and results in sensory and motor deficits [2,4,5,6]. Evidence suggests that the inflammatory events in the acute phase of spinal cord injury (SCI) exacerbate the initial trauma to the cord leading to poor functional recovery. As a result, minimizing the detrimental aspects of the inflammatory response after SCI is a promising treatment strategy. In this regard, immunoglobulin G (IgG) from pooled human serum is a promising treatment candidate. Though poorly characterized immuno-modulatory effects, IgG has been used clinically to treat neuroinflammatory disorders such as Guillain-Barré syndrome, but its effects in neurotrauma remain largely unexplored
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