Immunization with A91 peptide or copolymer‐1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury

Abstract

Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection.

Development of Protective Autoimmunity by Immunization with a Neural-Derived Peptide Is Ineffective in Severe Spinal Cord Injury

“…The present work demonstrated, for the first time, that A91 also induces a Th2 phenotype in experimental models of SCI. That finding provides substantial elements to explain, at least in part, our previous observations about the inhibitory effect of A91 immunization on iNOS gene expression and nitric oxide production [20]. Cytokines like IL-4 and IL-10 downregulate the expression of the iNOS gene, we hypothesized that this effect was caused by the action of a predominantly IL-4-secreting Th2 phenotype [21], [22].…”

Immunization with a Neural-Derived Peptide Protects the Spinal Cord from Apoptosis after Traumatic Injury

“…As we have already demonstrated the positive effect of A91 immunization on motor recovery (refer to [11, 13, 14]), we only evaluated the recovery 30 days after injury. The motor recovery observed in A91-immunized rats (8.72 ± 0.2; mean ± SD) was significantly higher than the one presented by PBS-immunized animals (6.2 ± 0.3; P < 0.001; Student's t -test; Figure 5(a)).…”

“…INDP is a new strategy that has shown to have an impact on several different destructive phenomena. A number of studies evaluating this strategy have demonstrated its positive effect on glutamate, lipid peroxidation, and nitric oxide reduction [8, 13, 30]. Furthermore, this strategy has rendered important evidence on its neurorestorative effects after SC injury [10, 31–33].…”

“…Evaluations were held 30 days after SC injury in order to correlate a reduction in apoptosis with functional recovery. For a more detailed evaluation of A91-induced neurological recovery please refer to [8, 13, 14]. …”

“…For instance, it has been shown that A91 diminishes lipid peroxidation [8]. This effect is due in part to a reduction in nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) gene expression [13]. The immune response elicited by A91 displays a Th2 phenotype, that is, capable of releasing brain-derived neurotrophic factor (BDNF) [14].…”