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Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.

Published version
Peer-reviewed

Type

Article

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Authors

Mottahedin, Amin 
Prag, Hiran A 
Dannhorn, Andreas 
Mair, Richard 

Abstract

Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.

Description

Funder: Bundesministerium für Bildung und Forschung

Keywords

Mice, Animals, Humans, Ischemic Stroke, Ischemia, Reperfusion Injury, Brain Ischemia, Stroke, Brain Injuries, Succinic Acid, Thrombectomy

Journal Title

Redox Biol

Conference Name

Journal ISSN

2213-2317
2213-2317

Volume Title

59

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (220257/Z/20/Z)
MRC (MC_UU_00028/4)
Medical Research Council (MC_UU_12022/6)
Cancer Research UK (A27453)
European Research Council (819920)