Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury

Abstract

BackgroundImmunization with neural derived peptides (INDP) as well as scar removal—separately—have shown to induce morphological and functional improvement after spinal cord injury (SCI). In the present study, we compared the effect of INDP alone versus INDP with scar removal on motor recovery, regeneration-associated and cytokine gene expression, and axonal regeneration after chronic SCI. Scar removal was conducted through a single incision with a double-bladed scalpel along the stump, and scar renewal was halted by adding α,α′-dipyridyl.ResultsDuring the chronic injury stage, two experiments were undertaken. The first experiment was aimed at testing the therapeutic effect of INDP combined with scar removal. Sixty days after therapeutic intervention, the expression of genes encoding for TNFα, IFNγ, IL4, TGFβ, BDNF, IGF1, and GAP43 was evaluated at the site of injury. Tyrosine hydroxylase and 5-hydroxytryptamine positive fibers were also studied. Locomotor evaluations showed a significant recovery in the group treated with scar removal + INDP. Moreover; this group presented a significant increase in IL4, TGFβ, BDNF, IGF1, and GAP43 expression, but a decrease of TNFα and IFNγ. Also, the spinal cord of animals receiving both treatments presented a significant increase of serotonergic and catecholaminergic fibers as compared to other the groups. The second experiment compared the results of the combined approach versus INDP alone. Rats receiving INDP likewise showed improved motor recovery, although on a lesser scale than those who received the combined treatment. An increase in inflammation and regeneration-associated gene expression, as well as in the percentage of serotonergic and catecholaminergic fibers was observed in INDP-treated rats to a lesser degree than those in the combined therapy group.ConclusionsThese findings suggest that INDP, both alone and in combination with scar removal, could modify the non-permissive microenvironment prevailing at the chronic phase of SCI, providing the opportunity of improving motor recovery.

Immunization with neural‐derived peptides increases neurogenesis in rats with chronic spinal cord injury

“…This increase was significantly associated with better sensory and motor recovery. Previous studies have shown that INDP induces both motor and sensitive restoration in both acute 29,30 and chronic 10,11 stages of injury. These beneficial effects could be the result of the increase in antiinflammatory and regeneration‐associated proteins as well as the reduction of pro‐inflammatory molecules which contribute inducing a favorable microenvironment for neurogenic processes.…”

“…The evaluation of gene expression (using qRT‐PCR) has shown that INDP induces a permissive microenvironment for neural restoration in the chronic stages of injury 10,11 . Based on these findings, we explored the induction of this microenvironment by directly analyzing the protein expression of antiinflammatory (IL‐4; IL‐10) and pro‐inflammatory (TNF‐α) cytokines.…”

“…Previous studies in our laboratory have shown that INDP induces axonal regeneration and functional recovery in the chronic phase of SCI 10 . On this basis, we tried to prove whether INDP is also capable of inducing neurogenesis.…”

“…In this context, immunization with neural‐derived peptides (INDP) has shown to induce neural restoration and functional recovery in the chronic stage of injury 9‐11 . This therapy induces a microenvironment characterized by a significant decrease in pro‐inflammatory as well as an increase in antiinflammatory cytokines.…”

“…Likewise, there is an important increase in the production of neurotrophic factors. These conditions have been associated with the regeneration of axons as well as with an improved motor recovery 10 . Since neurogenesis could be another possible mechanism by which INDP improves functional recovery, it is important to assess the effect of this therapy on the appearance of newly formed neurons in the chronic stages of SCI.…”