Chemokine inhibition in rat stab wound brain injury using antisense oligodeoxynucleotides

Traumatic injury to the central nervous system (CNS) results in the breakdown of the blood-brain barrier and recruitment of hematogenous cells at the site of injury. The role of chemokines in this process has been well recognized and they have been regarded as promising targets for development of anti-inflammatory therapies. The expression of monocyte chemoattractant protein (MCP-1), in particular, has been closely linked to macrophage infiltration following trauma in rat brain. In this study we determined whether inhibition of MCP-1 following stab wound injury would reduce macrophage infiltration. Stab wound injured Sprague-Dawley rats were infused with MCP-1 sense or antisense oligonucleotides using an Alzet miniosmotic pump (1 microl/h for 3 days). Three days following injury, widespread gliosis was observed in both groups of rats as judged by glial fibrillary acidic protein (GFAP) immunoreactivity. Immunohistochemistry showed significantly less staining for MCP-1 in antisense treated animals. In addition, the number of macrophages were reduced by 30% in the antisense compared to the sense treated animals (P < 0.05). These results demonstrate that modulation of MCP-1 expression in stab wound injury directly affects monocytic infiltration and provide a basis for MCP-1 inhibition as a therapeutic strategy for controlling inflammatory events of traumatic brain injury.