FPS-ZM1 is a RAGE-specific inhibitor, with a Ki value of 25nM[1]. FPS-ZM1 has been widely used in the research for improving the inflammatory response[2].
In vitro, FPS-ZM1 treatment (100nM; 1h) significantly inhibited the overexpression of RAGE induced by advanced glycation end product (AGE), RAGE-dependent microglial activation, nuclear translocation of nuclear factor κB p65 (NF-κB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor -α (TNF-α) and interleukin-1 β (IL-1β) in rat primary microglia[3]. Pretreated with 20μM FPS-ZM1 for 2 hours inhibited the expression of pro-inflammatory mediators and cytokines induced by lipopolysaccharide (LPS) in BV-2 cells[4].
In vivo, FPS-ZM1 treatment (1 mg/kg/day; i.p.) for 4 consecutive weeks reduced the production of amyloid-β (Aβ)1-40 and Aβ1-42 in Wistar rats and inhibited the increase of AGE-mediated Aβ metabolism-related proteins in the hippocampus[5]. FPS-ZM1 was administered orally at a dose of 2mg/kg/day for 2 months, reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLD), α -glutathione S-transferase (α-GST), alkaline phosphatase (ALP) and γ -glutamyl transpeptidase (GGT) in diabetic mice[6]. Intraperitoneal injection of FPS-ZM1 (3mg/kg/day) for 4 consecutive weeks can reduce lipid deposition in hepatocytes and lower the levels of mature SBP-1C, p-p65 nfκb and p-p38 MAPK in liver tissues in KK-Ay mice[7].
References:
[1]Zhou W, Hu W. Anti-neuroinflammatory agents for the treatment of Alzheimer’s disease[J]. Future Medicinal Chemistry, 2013, 5(13): 1559-1571.
[2] Shen L, Zhang T, Yang Y, et al. FPS-ZM1 alleviates neuroinflammation in focal cerebral ischemia rats via blocking ligand/RAGE/DIAPH1 pathway[J]. ACS chemical neuroscience, 2020, 12(1): 63-78.
[3] Shen C, Ma Y, Zeng Z, et al. RAGE-specific inhibitor FPS-ZM1 attenuates AGEs-induced neuroinflammation and oxidative stress in rat primary microglia[J]. Neurochemical research, 2017, 42: 2902-2911.
[4]Wang L, Zhao D, Wang H, et al. FPS-ZM1 inhibits LPS-induced microglial inflammation by suppressing JAK/STAT signaling pathway[J]. International immunopharmacology, 2021, 100: 108117.
[5] Hong Y, Shen C, Yin Q, et al. Effects of RAGE-specific inhibitor FPS-ZM1 on amyloid-β metabolism and AGEs-induced inflammation and oxidative stress in rat hippocampus[J]. Neurochemical research, 2016, 41: 1192-1199.
[6] Aslani S, Bahrambeigi S, Sanajou D. FPS-ZM1 Alleviates Circulating Indices of Liver Injury in Diet-Induced Type 2 Diabetic Mice[J]. Acta Medica Iranica, 2022: 40-45.
[7] Zhang M, Zhao W, Zhang Z, et al. FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c[J]. BMC Endocrine Disorders, 2024, 24(1): 164.
FPS-ZM1是一种特异性RAGE抑制剂，Ki值为25nM[1]。FPS-ZM1被广泛应用于改善炎症反应的研究中[2]。
在体外，100nM浓度的FPS-ZM1处理1小时能显著抑制大鼠原代小胶质细胞中由晚期糖基化终末产物（AGE）诱导的RAGE过表达，阻断RAGE依赖性小胶质细胞活化，抑制核因子κB p65（NF-κB p65）的核转位，并降低肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）等下游炎症介质的表达[3]。使用20μM浓度的FPS-ZM1预处理BV-2细胞2小时，可抑制脂多糖（LPS）诱导的促炎介质和细胞因子的表达[4]。
在体内，连续4周FPS-ZM1处理（1mg/kg/day；i.p.）能降低Wistar大鼠脑内淀粉样蛋白Aβ1-40和Aβ1-42的产生，并抑制海马区AGE介导的Aβ代谢相关蛋白升高[5]。FPS-ZM1经口服给药（2mg/kg/day）两个月后，糖尿病小鼠中的血清谷丙转氨酶（ALT）、谷草转氨酶（AST）、谷氨酸脱氢酶（GLD）、α-谷胱甘肽S-转移酶（α-GST）、碱性磷酸酶（ALP）和γ-谷氨酰转肽酶（GGT）水平均显著降低[6]。连续4周腹腔注射3mg/kg/day剂量的FPS-ZM1后，KK-Ay小鼠中的肝细胞脂质沉积减少，肝组织中成熟SBP-1C、p-p65 NF-κB和p-p38 MAPK水平下降[7]。