Reparixin is a noncompetitive allosteric inhibitor of the CXCL8 receptors CXCR1 and CXCR2, with IC50 values of 1nM and 10nM, respectively[1]. CXCR1 and CXCR2 are G protein-coupled receptors (GPCRs) that bind with high affinity to glutamine-leucine-arginine-positive (ELR+) chemokines. Blocking GPCRs appears to be an effective therapeutic strategy for treating ischemia/reperfusion injury. Therefore, reparixin is commonly used in the treatment and research of diseases such as acute lung injury, peritonitis, traumatic spinal cord injury and ischemia[2,3].
In vitro, treatment of undifferentiated human thyroid cancer 8505c and CAL62 cells with reparixin (10-30μM) for 8 days significantly inhibited cancer cell proliferation and reduced cell viability in a dose-dependent manner, while showing no significant effect on non-malignant thyroid cells[4]. Treatment of growth factor-deprived degenerating human MN (motor neuron)-like cells with reparixin (10μM) for 48h rescued glial cells from apoptosis and maintained neuronal morphology[5].
In vivo, reparixin (15mg/kg/day; twice a day) was administered to Sprague-Dawley rats with traumatic spinal cord injury (SCI) via initial intravenous injection followed by subcutaneous injections. After 7 days, reparixin significantly reduced the number of ED-1-positive cells at the injury site and decreased the expression of pro-inflammatory cytokines such as MIP-2 and TNF-α[6]. reparixin (30mg/kg/day; twice a day) was administered via intraperitoneal injection to CD1 nu/nu mice xenografted with 8505c thyroid cancer (TC) cells. After 4 weeks, tumor volume was significantly reduced[4]. Reparixin (15μg/g) was administered via intraperitoneal injection to C57BL/6 mice 15min before and 2h after lipopolysaccharide (LPS)-induced pulmonary inflammation, which significantly reduced neutrophil recruitment into the alveolar space after 24h[7].
References:
[1] BERTINI R, ALLEGRETTI M, BIZZARRI C, et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury[J]. Proceedings of the National Academy of Sciences, 2004, 101(32): 11791-11796.
[2] KIM H Y, CHOI J H, KANG Y J, et al. reparixin, an inhibitor of CXCR1 and CXCR2 receptor activation, attenuates blood pressure and hypertension-related mediators expression in spontaneously hypertensive rats[J]. Biological and Pharmaceutical Bulletin, 2011, 34(1): 120-127.
[3] THITIWUTHIKIAT P, TA-UEA T, PONGHAN T, et al. The protective effects of reparixin against endothelial ischemia-reperfusion injury[J]. International Journal of Health Sciences, 2022, 16(3): 20.
[4] LIOTTI F, DE PIZZOL M, ALLEGRETTI M, et al. Multiple anti-tumor effects of reparixin on thyroid cancer[J]. Oncotarget, 2017, 8(22): 35946.
[5] LA COGNATA V, GOLINI E, IEMMOLO R, et al. CXCR2 increases in ALS cortical neurons and its inhibition prevents motor neuron degeneration in vitro and improves neuromuscular function in SOD1G93A mice[J]. Neurobiology of Disease, 2021, 160: 105538.
[6] GORIO A, MADASCHI L, ZADRA G, et al. Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord[J]. The Journal of Pharmacology and Experimental Therapeutics, 2007, 322(3): 973-981.
[7] ZARBOCK A, ALLEGRETTI M, LEY K. Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice[J]. British journal of pharmacology, 2008, 155(3): 357-364.
Reparixin是CXCL8受体CXCR1和CXCR2的非竞争性变构抑制剂，IC50值分别为1nM和100nM[1]。CXCR1和CXCR2是G蛋白偶联受体（GPCR），以高亲和力结合glutamine-leucine-arginine-positive（ELR+）趋化因子，而阻断GPCR似乎是治疗缺血/再灌注损伤的有效治疗策略，故reparixin常被用于急性肺损伤、腹膜炎及创伤性脊髓损伤和缺血等疾病的治疗和研究[2,3]。
在体外，reparixin（10-30μM）处理人未分化甲状腺癌8505c和CAL62细胞8天，能以剂量依赖性方式显著抑制癌细胞的增殖并降低细胞活力，但对非恶性甲状腺细胞无显著影响[4]。Reparixin（10μM）处理生长因子剥夺的退化类人运动神经元（motor neuronal, MN）细胞48h，可挽救神经胶质细胞免于凋亡并维持神经元形态[5]。
在体内，reparixin（15mg/kg/day; twice a day）通过首次静脉给药，后续皮下注射的方式治疗创伤性脊髓损伤（SCI）的Sprague-Dawley大鼠，7天后显著减少了损伤部位ED-1阳性细胞的数量，降低了促炎细胞因子MIP-2和TNF-α等的表达[6]。Reparixin（30mg/kg/day; twice a day）通过腹膜注射治疗异种移植了8505c甲状腺癌（TC）细胞的CD1 nu/nu小鼠，4周后肿瘤的体积显著减小[4]。Reparixin（15μg/g）分别于脂多糖LPS诱发C57BL/6小鼠肺部炎症前15min和炎症后2h通过腹腔注射给药，24h后显著地减少了中性粒细胞向肺泡腔的募集[7]。