ML351 is a selective 15-lipoxygenase-1 (15-LOX-1; 12/15-LOX) inhibitor with an IC50 of 200nM[1]. 15-LOX-1 is a member of the lipid oxidase family that can trigger phospholipid peroxidation in the plasma membrane. By inhibiting 15-LOX-1, ML351 can reduce the production of harmful oxidative products in cells[2].
In vitro, HT-22 cells treated with ML351 (0-10μM) dose-dependently reversed glutamate-induced cell death[1]. ML351 (10μM) treatment of peritoneal macrophages (PMφ) cells for 2 h inhibited the inflammatory response induced by Kdo2-Lipid A and suppressed the mRNA expression of 12/15LOX and inducible nitric oxide synthase (iNOS )[3].
In vivo, ML351 (50 mg/kg) treated with acute heart failure mice by subcutaneous injection significantly reduced myocardial infarction size on days 1 and 5, increased CD11b expression, and reduced inflammatory responses in the heart and spleen [3]. ML351 (24 mg/kg) treated with intraperitoneal injection in non-obese diabetic (NOD) mice for 8 weeks reduced blood glucose levels, reduced oxidative stress markers in pancreatic β cells, and increased antioxidant enzyme levels [4]. ML351 (50μM/kg) treated with intraperitoneal injection in rats undergoing orthodontic treatment for 14 days strongly inhibited orthodontic-induced root resorption (OIRR) and suppressed the appearance of osteoclasts and odontoclasts [5].
References:
[1] Rai G, Joshi N, Perry S, et al. Discovery of ML351, a potent and selective inhibitor of human 15-lipoxygenase-1[J]. Probe Reports from the NIH Molecular Libraries Program [Internet], 2014.
[2] Cakir-Aktas C, Bodur E, Yemisci M, et al. 12/15 Lipoxygenase Inhibition Attenuates Neuroinflammation by Suppressing Inflammasomes[J]. Frontiers in cellular neuroscience, 2023, 17: 1277268.
[3] Tourki B, Black L M, Kain V, et al. Lipoxygenase inhibitor ML351 dysregulated an innate inflammatory response leading to impaired cardiac repair in acute heart failure[J]. Biomedicine & Pharmacotherapy, 2021, 139: 111574.
[4] Hernandez-Perez M, Chopra G, Fine J, et al. Inhibition of 12/15-lipoxygenase protects against β-cell oxidative stress and glycemic deterioration in mouse models of type 1 diabetes[J]. Diabetes, 2017, 66(11): 2875-2887.
[5] Nashiro-Oyakawa Y, Hotokezaka Y, Hotokezaka H, et al. Inhibition of 12/15-lipoxygenase reduces orthodontically induced root resorption in rats[J]. The Angle Orthodontist, 2024.
ML351是一种选择性15-脂氧合酶-1（15-LOX-1；12/15-LOX）抑制剂，IC50为200nM[1]。15-LOX-1是脂质氧化酶家族，可在质膜中引发磷脂的过氧化，ML351通过抑制15-LOX-1，可以减少细胞内有害氧化产物的产生[2]。
在体外，ML351（0-10 μM）处理HT-22细胞，剂量依赖性地逆转了谷氨酸诱导的细胞死亡[1]。ML351（10 μM）处理腹膜巨噬细胞（PMφ）细胞2 h，抑制了由 Kdo2-Lipid A诱导的炎症反应，抑制了12/15LOX和诱导型一氧化氮合酶（iNOS ）的mRNA表达[3]。
在体内，ML351（50 mg/kg）通过皮下注射治疗急性心力衰竭小鼠，在第1天和第5天显著减少了心肌梗死面积，升高了CD11b表达，降低了心脏和脾脏中的炎症反应[3]。ML351（24 mg/kg）通过腹腔注射治疗非肥胖糖尿病（NOD） 小鼠8周，降低了血糖水平，减少了胰腺β细胞中的氧化应激标志物，升高了抗氧化酶水平[4]。ML351（50 μM/kg）通过腹腔注射治疗进行牙齿正畸的大鼠14天，强烈抑制了正畸诱导的牙根吸收（OIRR），抑制了破骨细胞和破牙细胞的出现[5]。