Department of Anesthesiology, University of Maryland School of Medicine, United States of America.
Department of Emergency Medicine Program in Trauma, University of Maryland School of Medicine, United States of America.
Exp Neurol. 2020 Jun;328:113247. doi: 10.1016/j.expneurol.2020.113247. Epub 2020 Feb 12.
Mitochondria are both a primary source of reactive oxygen species (ROS) and a sensitive target of oxidative stress; damage to mitochondria can result in bioenergetic dysfunction and both necrotic and apoptotic cell death. These relationships between mitochondria and cell death are particularly strong in both acute and chronic neurodegenerative disorders. ROS levels are affected by both the production of superoxide and its toxic metabolites and by antioxidant defense mechanisms. Mitochondrial antioxidant activities include superoxide dismutase 2, glutathione peroxidase and reductase, and intramitochondrial glutathione. When intracellular conditions disrupt the homeostatic balance between ROS production and detoxification, a net increase in ROS and an oxidized shift in cellular redox state ensues. Cells respond to this imbalance by increasing the expression of genes that code for proteins that protect against oxidative stress and inhibit cytotoxic oxidation of proteins, DNA, and lipids. If, however, the genomic response to mitochondrial oxidative stress is insufficient to maintain homeostasis, mitochondrial bioenergetic dysfunction and release of pro-apoptotic mitochondrial proteins into the cytosol initiate a variety of cell death pathways, ultimately resulting in potentially lethal damage to vital organs, including the brain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a translational activating protein that enters the nucleus in response to oxidative stress, resulting in increased expression of numerous cytoprotective genes, including genes coding for mitochondrial and non-mitochondrial antioxidant proteins. Many experimental and some FDA-approved drugs promote this process. Since mitochondria are targets of ROS, it follows that protection against mitochondrial oxidative stress by the Nrf2 pathway of gene expression contributes to neuroprotection by these drugs. This document reviews the evidence that Nrf2 activation increases mitochondrial antioxidants, thereby protecting mitochondria from dysfunction and protecting neural cells from damage and death. New experimental results are provided demonstrating that post-ischemic administration of the Nrf2 activator sulforaphane protects against hippocampal neuronal death and neurologic injury in a clinically-relevant animal model of cardiac arrest and resuscitation.
线粒体既是活性氧（ROS）的主要来源，也是氧化应激的敏感靶点；线粒体损伤可导致生物能量功能障碍以及坏死和凋亡性细胞死亡。在急性和慢性神经退行性疾病中，线粒体与细胞死亡之间的这些关系尤为密切。ROS 水平受到超氧化物的产生及其有毒代谢物和抗氧化防御机制的影响。线粒体抗氧化活性包括超氧化物歧化酶 2、谷胱甘肽过氧化物酶和还原酶以及线粒体内部的谷胱甘肽。当细胞内条件破坏 ROS 产生和解毒之间的体内平衡时，ROS 的净增加和细胞氧化还原状态的氧化转移随之发生。细胞通过增加编码可防止氧化应激和抑制蛋白质、DNA 和脂质细胞毒性氧化的蛋白质的基因的表达来应对这种失衡。然而，如果线粒体氧化应激的基因组反应不足以维持体内平衡，则线粒体生物能量功能障碍和促凋亡线粒体蛋白释放到细胞质中会引发多种细胞死亡途径，最终导致对包括大脑在内的重要器官的潜在致命损伤。核因子红细胞 2 相关因子 2（Nrf2）是一种翻译激活蛋白，它会在氧化应激下进入细胞核，从而增加许多细胞保护基因的表达，包括编码线粒体和非线粒体抗氧化蛋白的基因。许多实验性和一些 FDA 批准的药物促进了这一过程。由于线粒体是 ROS 的靶标，因此 Nrf2 途径的基因表达对线粒体氧化应激的保护有助于这些药物的神经保护作用。本文综述了 Nrf2 激活增加线粒体抗氧化剂的证据，从而保护线粒体免受功能障碍，并保护神经细胞免受损伤和死亡。提供了新的实验结果，证明 Nrf2 激活剂萝卜硫素在心脏骤停和复苏的临床相关动物模型中，可防止海马神经元死亡和神经损伤。
