Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat

Spinal cord injury produced by mechanical contusion causes the onset of acu te and chronic degradative events. These include blood brain barrier disrup tion, edema, demyelination, axonal damage and neuronal cell death. Posttrau matic inflammation after spinal cord injury has been implicated in the seco ndary injury that ultimately leads to neurologic dysfunction, Studies after spinal cord contusion have shown expression of several chemokines early af ter injury and suggested a role for them in the ordered recruitment of infl ammatory cells at the lesion site (McTigue et at. [1998] J, Neurosci. Res. 53:368-376; Lee et al,, [2000] Neurochem Int). We have demonstrated previou sly that infusion of the broad-spectrum chemokine receptor antagonist (vMIP II) in the contused spinal cord initially attenuates leukocyte infiltration , suppresses' gliotic reaction and reduces neuronal damage after injury. Th ese changes are accompanied by increased expression of bcl-2, the endogenou s apoptosis inhibitor, and reduced neuronal apoptosis (Ghirnikar et al. [20 00] J. Neurosci. Res. 59,63-73). We demonstrate that 2 and 4 weeks of vMIPI I infusion in the contusion-injured spinal cord also results in decreased h ematogenous infiltration and is accompanied by reduced axonal degeneration in the gray matter. Luxol fast blue and MBP immunoreactivity indicated redu ced myelin breakdown in the dorsal and ventral funiculi, Increased neuronal survival in the ventral horns of vMIPII infused cords was seen along with increased bcl-2 staining in them. Immunohistochemical identification of fib er phenotypes showed increased presence of calcitonin gene related peptide, choline acetyl transferase and tyrosine hydroxylase positive fibers as wel l as increased GAP43 staining in treated cords. These results suggest that sustained reduction in posttraumatic cellular infiltration is beneficial fo r tissue survival. A preliminary report of this study has been published (E ng et al, [2000] J. Neurochem. 74(Suppl):S67B). In contrast to vMIPII, infu sion of MCP-1 (9-76), a N-terminal analog of the MCP-1 chemokine showed onl y a modest reduction in cellular infiltration at 14 and 21 dpi without sign ificant tissue survival after spinal cord contusion injury. Comparing data on tissue survival obtained with vMIPII and MCP-1 (9-76) further validate t he importance of the use of broad-spectrum antagonists in the treatment of spinal cord injury. Controlling the inflammatory reaction and providing a g rowth permissive environment would enhance regeneration and ultimately lead to neurological recovery after spinal cord injury. Published 2001 Wiley-Li ss, Inc.(dagger).