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.