N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice
Autor: | Victor M. Darley-Usmar, Giovanni Coppola, Domenico Praticò, Rajiv R. Ratan, Lauren Alin, Cassandra M. Wilkinson, Megan W. Bourassa, Stephanie C. Sanchez, David Brand, Amit Kumar, Frederick Colbourne, Theodore R. Holman, S. Thomas Carmichael, Saravanan S. Karuppagounder, Ginger L. Milne, Colby A. Nadeau, Yingxin Chen, John T. Pinto, Kristen Dietrich, Steve Perry |
---|---|
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Antioxidant medicine.medical_treatment Pharmacology Neuroprotection Acetylcysteine Lipid peroxidation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Prostaglandin E2 biology business.industry Glutathione 3. Good health 030104 developmental biology Neurology chemistry Mechanism of action Arachidonate 5-lipoxygenase biology.protein Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Annals of Neurology. 84:854-872 |
ISSN: | 0364-5134 |
Popis: | Author(s): Karuppagounder, Saravanan S; Alin, Lauren; Chen, Yingxin; Brand, David; Bourassa, Megan W; Dietrich, Kristen; Wilkinson, Cassandra M; Nadeau, Colby A; Kumar, Amit; Perry, Steve; Pinto, John T; Darley-Usmar, Victor; Sanchez, Stephanie; Milne, Ginger L; Pratico, Domenico; Holman, Theodore R; Carmichael, S Thomas; Coppola, Giovanni; Colbourne, Frederick; Ratan, Rajiv R | Abstract: ObjectivesN-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.MethodsHemin 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.ResultsNAC 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 E2 (PGE2 ).InterpretationNAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE2 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. |
Databáze: | OpenAIRE |
Externí odkaz: |