Marimastat is a broad-spectrum, orally active matrix metalloproteinase (MMP) inhibitor with IC50 values ranging from 3 to 13nM[1]. MMPs are a family of zinc-dependent proteolytic enzymes that are essential for tissue repair and remodeling, and are involved in various physiological processes including wound healing, angiogenesis, and cell migration[2]. Marimastat exerts its effects by inhibiting tumor metastasis and angiogenesis, and is commonly used in the research and treatment of pancreatic and gastric cancers[3,4].
In vitro, rat hippocampal neurons cultured in vitro on 7 days were pretreated with Marimastat (5nM, 0.5, 5, 40, and 100μM) for 30min, followed by stimulation with glutamate (50μM) for an additional 30min. Marimastat at 0.5μM inhibited MMP-9-dependent nectin-3 cleavage, while complete inhibition of nectin-3 cleavage was achieved at 5μM[5].
In vivo, C57BL/6J mice were administered Marimastat (100mg/kg; twice daily) by oral gavage for 1 week, followed by continued drug administration concomitant with CCl4 treatment for 6 weeks. Compared with the control group, the relative collagen content (hydroxyproline) in the liver increased by 25%, and the relative fibrotic area increased from 3.1% to 4.2%[6]. C57BL/6 mice fed a 60% high-fat diet for 9 weeks to induce hepatic steatosis were then treated with Marimastat (100mg/kg; twice daily) by oral gavage for 2 weeks, which significantly reduced fasting blood glucose levels[7].
References:
[1] RASMUSSEN H S, MCCANN P P. Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat[J]. Pharmacology & Therapeutics, 1997, 75(1): 69-75.
[2] NAGASE H, VISSE R, MURPHY G. Structure and function of matrix metalloproteinases and TIMPs[J]. Cardiovascular Research, 2006, 69(3): 562-573.
[3] KIMATA M, OTANI Y, KUBOTA T, et al. Matrix metalloproteinase inhibitor, marimastat, decreases peritoneal spread of gastric carcinoma in nude mice[J]. Japanese Journal of Cancer Research, 2002, 93(7): 834-841.
[4] STEWARD W P. Marimastat (BB2516): current status of development[J]. Cancer Chemotherapy and Pharmacology, 1999, 43(Suppl 1): S56-S60.
[5] PIJET B, KONOPKA A, REJMAK E, et al. The matrix metalloproteinase inhibitor marimastat inhibits seizures in a model of kainic acid-induced status epilepticus[J]. Scientific Reports, 2020, 10(1): 21314.
[6] DE MEIJER V E, SVERDLOV D Y, POPOV Y, et al. Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice[J]. PLoS One, 2010, 5(6): e11256.
[7] DE MEIJER V E, LE H D, MEISEL J A, et al. Tumor necrosis factor α-converting enzyme inhibition reverses hepatic steatosis and improves insulin sensitivity markers and surgical outcome in mice[J]. PLoS One, 2011, 6(9): e25587.
Marimastat是一种广谱的，具有口服活性的基质金属蛋白酶（MMP）抑制剂，IC50值为3~13nM[1]。MMP是一类依赖锌的蛋白水解酶，对组织修复和重塑至关重要，参与了包括伤口愈合、血管生成和细胞迁移等生理过程[2]。Marimastat通过抑制肿瘤转移和血管生成发挥作用，通常用于胰腺癌和胃癌的研究和治疗[3,4]。
在体外，Marimastat（5nM, 0.5, 5, 40, and 100μM）预处理在体外培养了7天的大鼠海马神经元30min，然后加入谷氨酸（50μM）继续刺激30min，0.5μM的Marimastat即可抑制MMP-9依赖性的nectin-3切割，而在5μM浓度下则可完全抑制nectin-3切割[5]。
在体内，Marimastat（100mg/kg; twice daily）通过口服灌胃给药C57BL/6J小鼠1周，后在继续给药的同时用CCl4处理6周，较对照组肝脏相对胶原含量（羟脯氨酸）增加25%，相对纤维化面积从3.1%增加至4.2%[6]。C57BL/6小鼠经60%高脂饮食喂养9周诱导肝脂肪变性后，给予Marimastat（100mg/kg; twice daily）口服灌胃治疗2周，显著降低了空腹血糖水平[7]。