Neutralization of the chemokine CXCL10 reduces apoptosis and increases axon sprouting after spinal cord injury

Abstract

Spinal cord injury (SCI) is followed by a secondary degenerative process that includes cell death. We have previously demonstrated that the chemokine CXCL10 is up-regulated following SCI and plays a critical role in T-lymphocyte recruitment to sites of injury and inhibition of angiogenesis; antibody-mediated functional blockade of CXCL10 reduced inflammation while enhancing angiogenesis. We hypothesized, based on these findings, that the injury environment established by anti-CXCL10 antibody treatment would support greater survival of neurons and enhance axon sprouting compared with the untreated, injured spinal cord. Here, we document gene array and histopathological data to support our hypothesis. Gene array analysis of treated and untreated tissue from spinal cord-injured animals revealed eight apoptosis-related genes with significant expression changes at 3 days postinjury. In support of these data, quantification of TUNEL-positive cells at 3 days postinjury indicated a 75% reduction in the number of dying cells in treated animals compared with untreated animals. Gene array analysis of treated and untreated tissue also revealed six central nervous system growth-related genes with significant expression changes in the brainstem at 14 days postinjury. In support of these data, quantification of anterograde-labeled corticospinal tract fibers indicated a 60-70% increase in axon sprouting caudal to the injury site in treated animals compared with untreated animals. These findings indicate that anti-CXCL10 antibody treatment provides an environment that reduces apoptosis and increases axon sprouting following injury to the adult spinal cord.

Voluntary running attenuates age-related deficits following SCI

“…The inflammatory response is a major component of secondary degeneration that follows the acute stages of SCI (Hausmann, 2003). Several studies support the notion that the inflammatory response is detrimental following injury, causing further loss of tissue that was spared by the initial mechanical insult (Glaser et al, 2004;Glaser et al, 2006;Gonzalez et al, 2003;Popovich et al, 1997;Popovich et al, 1999;Popovich et al, 2002;Taoka et al, 1997). This age-associated loss in neuroprotection and regulation of inflammation may drive the ageassociated increases in pathology and demyelination that we observed.…”

Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury

“…Accordingly, several studies have shown that therapies targeting various factors involved in the secondary degeneration cascade lead to tissue sparing and improved behavioral outcomes in spinal cord-injured animals (Bao et al, 2003;Cuzzocrea et al, 2006;Glaser et al, 2006). Much of the damage that occurs in the spinal cord following traumatic injury is due to the secondary effects of glutamate excitotoxicity, Ca 2ϩ overload, and oxidative stress, three mechanisms that take part in a spiraling interactive cascade ending in neuronal dysfunction and death (Anderson and Hall, 1993).…”

Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury

“…Accordingly, several studies have shown that therapies targeting various factors involved in the secondary degeneration cascade lead to tissue sparing and improved behavioral outcomes in spinal cord-injured animals (Bao et al, 2003;Cuzzocrea et al, 2006;Genovese et al, 2006b;Glaser et al, 2006). Much of the damage that occurs in the spinal cord after traumatic injury is due to the secondary effects of glutamate excitotoxicity, Ca 2ϩ overload, and oxidative stress, three mechanisms that take part in a spiraling interactive cascade ending in neuronal dysfunction and death (Tator, 1991;Anderson and Hall, 1993).…”