Abstract
It has been shown that the blockade of CXCR1 and CXCR2 receptors prevents ischemia/reperfusion damage in several types of vascular beds. Reparixin is a recently described inhibitor of human CXCR1/R2 and rat CXCR2 receptor activation. We applied reparixin in rats following traumatic spinal cord injury and determined therapeutic temporal and dosages windows. Treatment with reparixin significantly counteracts secondary degeneration by reducing oligodendrocyte apoptosis, migration to the injury site of neutrophils and ED-1-positive cells. The observed preservation of the white matter might also be secondary to the enhanced proliferation of NG2-positive cells. The expression of macrophage-inflammatory protein-2, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β was also counteracted, and the proliferation of glial fibrillary acidic protein-positive cells was markedly reduced. These effects resulted in a smaller post-traumatic cavity and in a significantly improved recovery of hind limb function. The best beneficial outcome of reparixin treatment required 7-day administration either by i.p. route (15 mg/kg) or subcutaneous infusion via osmotic pumps (10 mg/kg), reaching a steady blood level of 8 μg/ml. Methylprednisolone was used as a reference drug; such treatment reduced cytokine production but failed to affect the rate of hind limb recovery.
Footnotes
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This work was supported by the Italian Ministry of University and Research (MIUR) Grants COFIN 2003 and PRIN 2005.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.123679.
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ABBREVIATIONS: SCI, spinal cord injury; MIP-2, macrophage-inflammatory protein-2; MPSS, methylprednisolone; BBB, Basso, Beattie, and Bresnahan; GFAP, glial fibrillary acidic protein; NG2, oligodendrocyte progenitors marker; CNPase, 2′,3′-cyclic nucleotide 3′-phosphodiesterase; TUNEL, terminal deoxynucleotidyltransferase-mediated dUDP end labeling; hpf, histological power field; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; ANOVA, analysis of variance; TNF-α, tumor necrosis factor-α; Css, steady-state concentration; UTS, University of Trieste.
- Received March 30, 2007.
- Accepted June 28, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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