A toll-like receptor 9 antagonist restores below-level glial glutamate transporter expression in the dorsal horn following spinal cord injury

Abstract

Spinal cord (SC) trauma elicits pathological changes at the primary lesion and in regions distant from the injury epicenter. Therapeutic agents that target mechanisms at the injury site are likely to exert additional effects in these remote regions. We previously reported that a toll-like receptor 9 (TLR9) antagonist, oligodeoxynucleotide 2088 (ODN 2088), improves functional deficits and modulates the milieu at the epicenter in mice sustaining a mid-thoracic contusion. The present investigations use the same paradigm to assess ODN 2088-elicited alterations in the lumbar dorsal horn (LDH), a region remote from the injury site where SCI-induced molecular alterations have been well defined. We report that ODN 2088 counteracts the SCI-elicited decrease in glial glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT1) levels, whereas the levels of the neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) and astroglial GABA transporter 3 (GAT3) were unaffected. The restoration of GLAST and GLT1 was neither paralleled by a global effect on astrocyte and microglia activation nor by changes in the expression of cytokines and growth factors reported to regulate these transporters. We conclude that the effects of intrathecal ODN 2088 treatment extend to loci beyond the epicenter by selectively targeting glial glutamate transporters.

Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury

“…Importantly, the investigations on mice sustaining a SCI indicate that treatment with ODN 2088 fosters M2 macrophages at the glial scar. This finding complements our earlier report demonstrating alterations in the glial scar in response to ODN 2088 [30,82]. It remains to be determined whether the in vivo effects of ODN 2088 on macrophage polarization are the outcome of direct inhibition of TLR9 in astrocytes or mediated through effects on other cells such as neurons, microglia, and infiltrating immune cells, which also express TLR9.…”

Pathological pain processing in mouse models of multiple sclerosis and spinal cord injury: contribution of plasma membrane calcium ATPase 2 (PMCA2)

“…The reduction in PMCA2 levels in the lumbar DH of mice sustaining a SCI could be the result of cellular and molecular changes that are different than those occurring in EAE because in the SCI model, infiltrating immune cells are not present in the lumbar SC [60]. The lumbar region is considerably remote from the lesion site where infiltrating immune cells are abundant [60]. However, persistent microglial activation is observed in the lumbar SC at 28 dpi, a sub-acute SCI phase during which we evaluated both pain and PMCA2 protein levels.…”

Acute spinal cord injury: Pathophysiology and pharmacological intervention (Review)

“…Activation of NMDA and non-NMDA can serve a crucial role in the excitotoxic damage following SCI ( 84 ). Along with traumatic disorders, non-traumatic CNS disorders have quickened the development of associated pharmacological interventions.…”