Paquinimod (ABR-215757) binds S100A9 and inhibits its interaction with TLR4/MD2 and RAGE[1-2].
The addition of paquinimod(350 μM paquinimod;30 min preincubated) significantly inhibited the up-regulated levels of IL-6 and IL-8 protein in synovium due to S100A9, but had no inhibitory effect on TNF-α[7].
Mice prophylactically treated with paquinimod(10 mg/kg/day;14days;added into the drinking water) exhibited detectable but mitigated signs of colitis, as determined by a reduced trend in weight loss, reduced colonic shortening and inflammation in the colons compared to DSS-only treated mice. Paquinimod treatment also prevented the upregulation of Lcn2 and S100A8/A9 in the brain in DSS-treated mice[3]. In a meningitis model, MRP14-deficient mice showed a better resolution of inflammation during antibiotic therapy. Treatment with the MRP14 antagonist paquinimod(10 mg/kg) reduced inflammation and disease severity significantly, reaching levels comparable to those achieved after genetic depletion of MRP14[4]. Preventive treatment with the paquinimod (ABR-215757) (25 mg/kg;5days;added into the drinking water) during the first 5 days after induction of experimental autoimmune encephalomyelitis is sufficient to significantly ameliorate disease symptoms[5]. Paquinimod treatment can significantly inhibit progression of insulitis to T1D in the NOD mouse[6].
References:
[1]. Bj?rk P, Bj?rk A,et,al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009 Apr 28;7(4):e97. doi: 10.1371/journal.pbio.1000097. PMID: 19402754; PMCID: PMC2671563.
[2]. Gong H, Su WJ, et,al.Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice. J Neuroinflammation. 2018 Sep 4;15(1):252. doi: 10.1186/s12974-018-1296-0. PMID: 30180864; PMCID: PMC6122683.
[3]. Talley S, Valiauga R, et,al.DSS-induced inflammation in the colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod. J Neuroinflammation. 2021 Nov 10;18(1):263. doi: 10.1186/s12974-021-02317-6. PMID: 34758843; PMCID: PMC8578918.
[4]. Wache C, Klein M, et,al.Myeloid-related protein 14 promotes inflammation and injury in meningitis. J Infect Dis. 2015 Jul 15;212(2):247-57. doi: 10.1093/infdis/jiv028. Epub 2015 Jan 20. PMID: 25605866.
[5]. Helmersson S, Sundstedt A, et,al.Amelioration of experimental autoimmune encephalomyelitis by the quinoline-3-carboxamide paquinimod: reduced priming of proinflammatory effector CD4(+) T cells. Am J Pathol. 2013 May;182(5):1671-80. doi: 10.1016/j.ajpath.2013.01.032. Epub 2013 Mar 16. PMID: 23506849.
[6]. Tahvili S, T?rngren M, et,al. Paquinimod prevents development of diabetes in the non-obese diabetic (NOD) mouse. PLoS One. 2018 May 9;13(5):e0196598. doi: 10.1371/journal.pone.0196598. PMID: 29742113; PMCID: PMC5942776.
[7]. Schelbergen RF, Geven EJ, et,al.Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis. Ann Rheum Dis. 2015 Dec;74(12):2254-8. doi: 10.1136/annrheumdis-2014-206517. Epub 2015 May 12. PMID: 25969431.
Paquinimod (ABR-215757) 结合 S100A9 并抑制其与 TLR4/MD2 和 RAGE 的相互作用[1-2]。
添加帕喹莫德（350 μM 帕喹莫德；30 分钟预孵育）可显着抑制 S100A9 引起的滑膜中 IL-6 和 IL-8 蛋白水平上调,但对 TNF-α 无抑制作用 [7].
用帕喹莫德（10 毫克/千克/天；14 天；添加到饮用水中）进行预防性治疗的小鼠表现出可检测到但减轻的结肠炎迹象,这是由体重减轻趋势减少、结肠缩短和结肠炎症减少来确定的与仅接受 DSS 治疗的小鼠相比。 Paquinimod 治疗还阻止了 DSS 治疗小鼠大脑中 Lcn2 和 S100A8/A9 的上调[3]。在脑膜炎模型中,MRP14 缺陷小鼠在抗生素治疗期间表现出更好的炎症消退。使用 MRP14 拮抗剂帕喹莫德 (10 mg/kg) 治疗可显着降低炎症和疾病严重程度,达到与 MRP14 基因缺失后达到的水平相当[4]。在诱导实验性自身免疫性脑脊髓炎后的前 5 天内,使用帕喹莫德 (ABR-215757)（25 mg/kg；5 天；添加到饮用水中）进行预防性治疗足以显着改善疾病症状[5]。帕喹莫德治疗可显着抑制 NOD 小鼠胰岛炎进展为 T1D[6]。