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"EFFECTS OF A TOLL-LIKE RECEPTOR (TLR) 9 ANTAGONIST IN REGIONS REMOTE FROM THE LESION CORE FOLLOWING SPINAL CORD INJURY"

by
Alexandra Pallottie
Cell Biology, Neuroscience and Physiology Program
B.A. 2011, Lafayette College, Easton, PA


Thesis Advisors:
Stella Elkabes, Ph.D.
Associate Professor
Department of Neurological Surgery
&
Robert F. Heary, M.D.
Professor
Department of Neurological Surgery

Wednesday, November 15, 2017
10:30 A.M., Cancer Center, G-1196


Abstract

Spinal cord (SC) trauma elicits pathological changes at both the primary lesion site and in regions distant from the injury epicenter. Therapeutic agents that target pathophysiological mechanisms at the lesion are likely to exert additional effects in remote regions. In earlier studies, we reported that a toll-like receptor 9 (TLR9) antagonist, CpG ODN 2088, improves functional deficits and positively modulates the cellular and molecular milieu at the epicenter in mice sustaining a mid-thoracic contusion injury. The present investigations used the same experimental paradigm to assess CpG ODN 2088-elicited alterations in a region apart from the primary injury site. We focused on the lumbar dorsal horn (LDH) because SCI-induced molecular alterations have been well delineated, especially in the context of mechanisms underlying below-level neuropathic pain. We analyzed the effect of intrathecal CpG ODN 2088 treatment on glutamate transporters (GluTs) and receptors which have been implicated in such mechanisms. We report that intrathecal CpG ODN 2088 treatment counteracts the SCI-elicited decrease in astroglial glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT1) levels in the LDH. In contrast, the levels of the neuronal GluT, excitatory amino acid carrier 1 (EAAC1), were not modulated. The restoration of GLAST and GLT1 by the antagonist 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 GLAST and/or GLT1 levels. We conclude that the positive effects of intrathecal CpG ODN 2088 treatment are not restricted to the lesion site and include additional loci beyond the bounds of the injury epicenter, selectively targeting glial GluTs.


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