N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Abstract

Objectives N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. Methods Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5‐lipoxygenase (ALOX5) knockout mice, and viral‐gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC. Results NAC prevented hemin‐induced ferroptosis by neutralizing toxic lipids generated by arachidonate‐dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione‐dependent enzymes such as glutathione S ‐transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E 2 (PGE 2 ). Interpretation NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE 2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854–872

Ferroptosis: past, present and future

“…In the study of hemorrhagic stroke, N-acetylcysteine (NAC) inhibits heme-induced ferroptosis in brain cells by neutralizing toxic lipids produced by arachidonatedependent ALOX5 activity. Early application of NAC after intracerebral hemorrhage can reduce neuronal mortality and effectively improve the prognosis of patients 73 . Other studies have found that the level of GPX4 in brain tissue decreases significantly 24 h after cerebral hemorrhage, while increasing the level of GPX4 significantly reduces neuronal dysfunction, brain edema, blood-brain barrier damage, oxidative stress and inflammatory damage after cerebral hemorrhage, and the application of the ferroptosis inhibitor Fer-1 also significantly reduces the extent of secondary brain injury after cerebral hemorrhage 74 .…”

Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells

“…A full understanding of the mechanisms hibernator cells use to sustain mitochondrial function and avoid ferroptosis during hypothermia may reveal the specific cellular protection mechanism, which may ultimately lead to the development of novel approaches to limit organ damage in, for example, transplantation, major surgery or cardiac arrest. Beyond these applications, this may possibly even apply to ferroptosis associated stress conditions comparable to hypothermia, such as stroke [38] and acute kidney injury [39].…”

MiR-137 Boosts the Neuroprotective Effect of Endothelial Progenitor Cell Derived-Exosomes in Oxyhemoglobin Treated SH-SY5Y Cells Partially via COX2/PGE2 Pathway

“…In studies of ICH, COX2 and PGE2 were both reported to be involved in ferroptosis in the brain. Qian et al considered that COX2 could serve as a biomarker of ferroptosis [6,47]. Thus, we considered that the COX2/PGE2 pathway might also participate in the regulation of the mechanism of miR-137 in ferroptosis.…”