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Ryan, F.* ; Blex, C.* ; Ngo, T.D.* ; Kopp, M.A.* ; Michalke, B. ; Venkataramani, V.* ; Curran, L.* ; Schwab, J.M.* ; Ruprecht, K.* ; Otto, C.* ; Jhelum, P.* ; Kroner, A.* ; David, S.*

Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury.

Acta Neuropathol. 147:106 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Antioxidants ; Ferritin ; Iron Toxicity ; Lipid Peroxidation ; Ncoa4 ; Spinal Cord Injury; Cell-death; Glutathione-peroxidase; Iron Homeostasis; Secondary Damage; Recovery; Ceruloplasmin; Metabolism; Locomotion; Receptor; Roles
ISSN (print) / ISBN 0001-6322
e-ISSN 1432-0533
Zeitschrift Acta Neuropathologica
Quellenangaben Band: 147, Heft: 1, Seiten: , Artikelnummer: 106 Supplement: ,
Verlag Springer
Verlagsort One New York Plaza, Suite 4600, New York, Ny, United States
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Analytical BioGeoChemistry (BGC)
Förderungen Hunt and Curtis Endowment
Canadian Institutes of Health Research
WFL
WFL-RF grant
Else Kroner-Fresenius-Stiftung Foundation
Deutsche Forschungsgemeinschaft (German Research Foundation)
NIH/NINDS
Wings for Life Spinal Cord Research Foundation (WFL, Salzburg, Austria)