SB 225002 is a potent and selective CXCR2 chemokine receptor antagonist that inhibits the binding of 125I-IL-8 (125I-labeled interleukin 8) and CXCR2 with an IC50 value of 22nM[1].
In HL60 cells, SB 225002 potently prevented IL-8 and GROα-induced neutrophil chemotaxis. In cells expressing predominantly CXCR2 (~80%) and to a lesser extent CXCR1 (~20%) receptors, SB 225002 produces concentration-dependent inhibition of IL-8 and GROα-mediated calcium mobilization, with IC50 values of 8 and 10nM, respectively[1]. GROβ enhances transcription of EGR-1, via the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which can be blocked by an antagonist of CXCR2 (SB 225002). 400nM of SB 225002 blocked CXCR2 signaling in WHCO1 cells and significantly reduced cell proliferation (40%-50%)[2].
SB 225002 (1.39-5.5μg/kg/min）selectively blocks IL-8-induced neutrophil marginalization in a neutrophil sequestration rabbit model[1]. SB 225002 (2mg/kg) did not affect ischemic brain damage in lipid-normal wild-type mice, but reversed the increased brain damage in hyperlipidemic ApoE-/- mice[3]. In a young rat model of lipopolysaccharide (LPS)-sensitized hypoxic-ischemic (HI) cerebral white matter injury, SB 225002 (1 or 3mg/kg) significantly attenuated microglia activation, blood-brain barrier (BBB) injury, and astrocyte hyperplasia in the white matter after LPS-sensitized HI[4].
References:
[1] White J R, Lee J M, Young P R, et al. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration[J]. Journal of Biological Chemistry, 1998, 273(17): 10095-10098.
[2] Wang B, Hendricks D T, Wamunyokoli F, et al. A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer[J]. Cancer research, 2006, 66(6): 3071-3077.
[3] Herz J, Sabellek P, Lane TE, Gunzer M, Hermann DM, Doeppner TR. Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice. Stroke. 2015 Oct;46(10):2916-25.
[4] Wang LY, Tu YF, Lin YC, Huang CC. CXCL5 signaling is a shared pathway of neuroinflammation and blood-brain barrier injury contributing to white matter injury in the immature brain. J Neuroinflammation. 2016 Jan 6;13:6.
SB 225002是一种有效的选择性CXCR2趋化因子受体拮抗剂，可抑制125I-IL-8（125I标记的白细胞介素8）和CXCR2的结合，IC50值为22nM[1]。
在HL60细胞中，SB 225002有效阻止IL-8和GROα诱导的中性粒细胞趋化性。在主要表达CXCR2（~80%）和少量表达CXCR1（~20%）受体的细胞中，SB 225002对IL-8和GROα介导的钙动员产生浓度依赖性抑制，IC50值分别为8和10nM[1]。GROβ通过细胞外信号调节激酶1/2（ERK1/2）途径增强EGR-1的转录，该途径可被SB 225002阻断。400nM的SB 225002可阻断WHCO1细胞中的CXCR2信号，可显著降低细胞增殖（40%-50%）[2]。
在中性粒细胞隔离兔子模型中SB 225002（1.39-5.5μg/kg/min）选择性阻断IL-8诱导的中性粒细胞边缘化[1]。SB 225002（2mg/kg）不会影响血脂正常的野生型小鼠的缺血性脑损伤，但逆转了高脂血症ApoE −/−小鼠中增加的脑损伤[3]。在LPS致敏HI（缺氧缺血）脑白质损伤的幼鼠模型中，SB 225002（1或3mg/kg）显著减轻小胶质细胞活化、BBB损伤和LPS致敏HI后白质中的星形胶质细胞增生[4]。