title: The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis.
abstract: 5-Lipoxygenase (5-LOX) inhibitors have been shown to be protective in several neurodegenerative disease models; however, the underlying mechanisms remain unclear. We investigated whether 5-LOX inhibitor zileuton conferred direct neuroprotection against glutamate oxidative toxicity by inhibiting ferroptosis, a newly identified iron-dependent programmed cell death. Treatment of HT22 mouse neuronal cell line with glutamate resulted in significant cell death, which was inhibited by zileuton in a dose-dependent manner. Consistently, zileuton decreased glutamate-induced production of reactive oxygen species but did not restore glutamate-induced depletion of glutathione. Moreover, the pan-caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVAD-fmk) neither prevented HT22 cell death induced by glutamate nor affected zileuton protection against glutamate oxidative toxicity, suggesting that zileuton did not confer neuroprotection by inhibiting caspase-dependent apoptosis. Interestingly, glutamate-induced HT22 cell death was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. Moreover, zileuton protected HT22 neuronal cells from erastin-induced ferroptosis. However, we did not observe synergic protective effects of zileuton and ferrostatin-1 on glutamate-induced cell death. These results suggested that both the 5-LOX inhibitor zileuton and the ferropotosis inhibitor ferrostatin-1 acted through the same cascade to protect against glutamate oxidative toxicity. In conclusion, our results suggested that zileuton protected neurons from glutamate-induced oxidative stress at least in part by inhibiting ferroptosis.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yuyao
authors.initials: Y
authors.lastname: Li
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002460:Cell Line; D003514:Cyclohexylamines / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000066829:Neuroprotection; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010655:Phenylenediamines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D003514:Cyclohexylamines; D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; C573944:ferrostatin-1; D018698:Glutamic Acid; D007501:Iron; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea