Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, 92093 La Jolla, CA, USA.
Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, 92093 La Jolla, CA, USA.
Mol Metab. 2020 Feb;32:122-135. doi: 10.1016/j.molmet.2019.11.019. Epub 2019 Dec 13.
Cerebral ischemia/reperfusion (IR) drives oxidative stress and injurious metabolic processes that lead to redox imbalance, inflammation, and tissue damage. However, the key mediators of reperfusion injury remain unclear, and therefore, there is considerable interest in therapeutically targeting metabolism and the cellular response to oxidative stress.
The objective of this study was to investigate the molecular, metabolic, and physiological impact of itaconate treatment to mitigate reperfusion injuries in in vitro and in vivo model systems. We conducted metabolic flux and bioenergetic studies in response to exogenous itaconate treatment in cultures of primary rat cortical neurons and astrocytes. In addition, we administered itaconate to mouse models of cerebral reperfusion injury with ischemia or traumatic brain injury followed by hemorrhagic shock resuscitation. We quantitatively characterized the metabolite levels, neurological behavior, markers of redox stress, leukocyte adhesion, arterial blood flow, and arteriolar diameter in the brains of the treated/untreated mice.
We demonstrate that the "immunometabolite" itaconate slowed tricarboxylic acid (TCA) cycle metabolism and buffered redox imbalance via succinate dehydrogenase (SDH) inhibition and induction of anti-oxidative stress response in primary cultures of astrocytes and neurons. The addition of itaconate to reperfusion fluids after mouse cerebral IR injury increased glutathione levels and reduced reactive oxygen/nitrogen species (ROS/RNS) to improve neurological function. Plasma organic acids increased post-reperfusion injury, while administration of itaconate normalized these metabolites. In mouse cranial window models, itaconate significantly improved hemodynamics while reducing leukocyte adhesion. Further, itaconate supplementation increased survival in mice experiencing traumatic brain injury (TBI) and hemorrhagic shock.
We hypothesize that itaconate transiently inhibits SDH to gradually "awaken" mitochondrial function upon reperfusion that minimizes ROS and tissue damage. Collectively, our data indicate that itaconate acts as a mitochondrial regulator that controls redox metabolism to improve physiological outcomes associated with IR injury.
脑缺血/再灌注（IR）引发氧化应激和损伤性代谢过程，导致氧化还原失衡、炎症和组织损伤。然而，再灌注损伤的关键介质仍不清楚，因此，人们对靶向治疗代谢和细胞对氧化应激的反应有很大的兴趣。
本研究旨在研究衣康酸治疗对体外和体内模型系统减轻再灌注损伤的分子、代谢和生理影响。我们对原代大鼠皮质神经元和星形胶质细胞培养物中外源衣康酸处理的代谢通量和生物能进行了研究。此外，我们在缺血或创伤性脑损伤后继发出血性休克复苏的小鼠模型中给予衣康酸。我们定量分析了处理/未处理小鼠大脑中的代谢物水平、神经行为、氧化应激标志物、白细胞黏附、动脉血流和小动脉直径。
我们证明，“免疫代谢物”衣康酸通过琥珀酸脱氢酶（SDH）抑制减缓三羧酸（TCA）循环代谢，并通过诱导抗氧化应激反应来缓冲氧化还原失衡在星形胶质细胞和神经元的原代培养物中。在小鼠脑 IR 损伤后的再灌注液中加入衣康酸可增加谷胱甘肽水平并减少活性氧/氮物种（ROS/RNS），从而改善神经功能。再灌注损伤后血浆有机酸增加，而衣康酸给药可使这些代谢物正常化。在小鼠颅窗模型中，衣康酸可显著改善血液动力学，同时减少白细胞黏附。此外，衣康酸补充可提高经历创伤性脑损伤（TBI）和出血性休克的小鼠的存活率。
我们假设衣康酸暂时抑制 SDH，在再灌注时逐渐“唤醒”线粒体功能，从而最大限度地减少 ROS 和组织损伤。总的来说，我们的数据表明，衣康酸作为一种线粒体调节剂，控制氧化还原代谢，改善与 IR 损伤相关的生理结果。
