Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.
Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.
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DOI：
10.1016/j.redox.2023.102600
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发表时间：
2023-03
期刊：
影响因子：
11.4
通讯作者：
Krieg, Thomas
中科院分区：
文献类型：
--
作者：
Mottahedin, Amin;Prag, Hiran A.;Dannhorn, Andreas;Mair, Richard;Schmidt, Christina;Yang, Ming;Sorby-Adams, Annabel;Lee, Jordan J.;Burger, Nils;Kulaveerasingam, Duvaraka;Huang, Margaret M.;Pluchino, Stefano;Peruzzotti-Jametti, Luca;Goodwin, Richard;Frezza, Christian;Murphy, Michael P.;Krieg, Thomas
目前对急性缺血性卒中的治疗旨在恢复缺血区域的正常灌注，但也可引起显著的缺血-再灌注（IR）损伤。中风实验模型中的先前数据表明，缺血导致琥珀酸积累，并且在再灌注时，积累的琥珀酸被琥珀酸脱氢酶（SDH）快速氧化，以驱动线粒体复合物I处的超氧化物产生。尽管这一过程引发IR损伤并引起进一步的组织损伤，但靶向琥珀酸代谢以使IR损伤最小化的潜力仍未被探索。使用定量和非靶向的高分辨率代谢组学，我们显示了暴露于缺血离体的人和小鼠脑中琥珀酸的时间依赖性积累。在缺血性中风/机械血栓切除术的小鼠模型中，质谱成像（MSI）显示琥珀酸积累仅限于缺血区域，并且积累的琥珀酸在再灌注时迅速氧化。再灌注时通过全身输注SDH抑制剂丙二酸酯靶向琥珀酸氧化导致急性脑损伤的剂量依赖性降低。总之，这些发现支持靶向琥珀酸代谢后再灌注，以减少IR损伤作为一个有价值的辅助缺血性卒中的机械血栓切除术。
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.
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影响因子：
16.6
作者：
Yin Z;Burger N;Kula-Alwar D;Aksentijević D;Bridges HR;Prag HA;Grba DN;Viscomi C;James AM;Mottahedin A;Krieg T;Murphy MP;Hirst J
通讯作者：
Hirst J
影响因子：
2.1
作者：
Tang, Yuan;Horikoshi, Masaaki;Li, Wenxuan
通讯作者：
Li, Wenxuan
DOI：
10.1016/s1474-4422(12)70203-x
发表时间：
2012-10
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Lansberg MG;Straka M;Kemp S;Mlynash M;Wechsler LR;Jovin TG;Wilder MJ;Lutsep HL;Czartoski TJ;Bernstein RA;Chang CW;Warach S;Fazekas F;Inoue M;Tipirneni A;Hamilton SA;Zaharchuk G;Marks MP;Bammer R;Albers GW;DEFUSE 2 study investigators
通讯作者：
DEFUSE 2 study investigators
利用 3D 磁共振波谱对急性中风进行快速高分辨率代谢成像
DOI：
10.1093/brain/awaa264
发表时间：
2020-12-05
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Li Y;Wang T;Zhang T;Lin Z;Li Y;Guo R;Zhao Y;Meng Z;Liu J;Yu X;Liang ZP;Nachev P
通讯作者：
Nachev P
影响因子：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.