Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord
Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord
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DOI：
10.1124/jpet.107.123679
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发表时间：
2007-09-01
影响因子：
3.5
通讯作者：
Di Giulio, Anna Maria
中科院分区：
文献类型：
--
作者：
Gorio, Alfredo;Madaschi, Laura;Di Giulio, Anna Maria
已经表明，CXCR 1和CXCR 2受体的阻断可防止几种类型血管床的缺血/再灌注损伤。瑞帕利辛是最近描述的人CXCR 1/R2和大鼠CXCR 2受体活化的抑制剂。我们在大鼠脊髓损伤后应用了瑞帕瑞辛，并确定了治疗时间窗和剂量窗。用瑞帕瑞辛治疗通过减少少突胶质细胞凋亡、中性粒细胞和艾德-1阳性细胞向损伤部位的迁移而显著抵消继发性变性。观察到的白色物质的保存也可能继发于NG 2阳性细胞的增殖增强。巨噬细胞炎性蛋白-2、肿瘤坏死因子-α、白细胞介素（IL）-6和IL-1 β的表达也被抵消，并且胶质细胞酸性蛋白阳性细胞的增殖显著减少。这些作用导致创伤后空腔较小，后肢功能恢复显著改善。瑞帕瑞辛治疗的最佳有益结果需要通过腹膜内途径（15 mg/kg）或通过渗透泵皮下输注（10 mg/kg）给药7天，达到8 μ g/ml的稳定血液水平。甲基强的松龙被用作参考药物;这种治疗减少了细胞因子的产生，但未能影响后肢恢复的速度。
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-alpha, interleukin (IL)-6, and IL-1 beta 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 mu g/ml. Methylprednisolone was used as a reference drug; such treatment reduced cytokine production but failed to affect the rate of hind limb recovery.