Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Materia Medica, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Education Ministry Key Laboratory of Medical Electrophysiology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau SAR, 99078, China.
Oxid Med Cell Longev. 2022 Apr 4;2022:1015791. doi: 10.1155/2022/1015791. eCollection 2022.
Traumatic brain injury (TBI), known as mechanical damage to the brain, impairs the normal function of the brain seriously. Its clinical symptoms manifest as behavioral impairment, cognitive decline, communication difficulties, etc. The pathophysiological mechanisms of TBI are complex and involve inflammatory response, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, and so on. Among them, oxidative stress, one of the important mechanisms, occurs at the beginning and accompanies the whole process of TBI. Most importantly, excessive oxidative stress causes BBB disruption and brings injury to lipids, proteins, and DNA, leading to the generation of lipid peroxidation, damage of nuclear and mitochondrial DNA, neuronal apoptosis, and neuroinflammatory response. Transcription factor NF-E2 related factor 2 (Nrf2), a basic leucine zipper protein, plays an important role in the regulation of antioxidant proteins, such as oxygenase-1(HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and glutathione peroxidase (GPx), to protect against oxidative stress, neuroinflammation, and neuronal apoptosis. Recently, emerging evidence indicated the knockout (KO) of Nrf2 aggravates the pathology of TBI, while the treatment of Nrf2 activators inhibits neuronal apoptosis and neuroinflammatory responses via reducing oxidative damage. Phytochemicals from fruits, vegetables, grains, and other medical herbs have been demonstrated to activate the Nrf2 signaling pathway and exert neuroprotective effects in TBI. In this review, we emphasized the contributive role of oxidative stress in the pathology of TBI and the protective mechanism of the Nrf2-mediated oxidative stress response for the treatment of TBI. In addition, we summarized the research advances of phytochemicals, including polyphenols, terpenoids, natural pigments, and otherwise, in the activation of Nrf2 signaling and their potential therapies for TBI. Although there is still limited clinical application evidence for these natural Nrf2 activators, we believe that the combinational use of phytochemicals such as Nrf2 activators with gene and stem cell therapy will be a promising therapeutic strategy for TBI in the future.
创伤性脑损伤（TBI），又称脑的机械性损伤，严重损害大脑的正常功能。其临床症状表现为行为障碍、认知能力下降、沟通困难等。TBI 的病理生理机制复杂，涉及炎症反应、氧化应激、线粒体功能障碍、血脑屏障（BBB）破坏等。其中，氧化应激是重要机制之一，发生在 TBI 的开始，并伴随整个过程。最重要的是，过度的氧化应激导致 BBB 破坏，并对脂质、蛋白质和 DNA 造成损伤，导致脂质过氧化、核和线粒体 DNA 损伤、神经元凋亡和神经炎症反应的产生。转录因子 NF-E2 相关因子 2（Nrf2），一种碱性亮氨酸拉链蛋白，在调节抗氧化蛋白方面发挥着重要作用，如氧化酶-1（HO-1）、NAD（P）H 醌氧化还原酶 1（NQO1）和谷胱甘肽过氧化物酶（GPx），以对抗氧化应激、神经炎症和神经元凋亡。最近，有证据表明 Nrf2 的敲除（KO）加重了 TBI 的病理，而 Nrf2 激活剂的治疗通过减少氧化损伤抑制神经元凋亡和神经炎症反应。来自水果、蔬菜、谷物和其他草药的植物化学物质已被证明能激活 Nrf2 信号通路，并在 TBI 中发挥神经保护作用。在这篇综述中，我们强调了氧化应激在 TBI 病理中的作用以及 Nrf2 介导的氧化应激反应对 TBI 治疗的保护机制。此外，我们总结了植物化学物质（包括多酚、萜类化合物、天然色素等）在激活 Nrf2 信号通路及其在 TBI 潜在治疗中的研究进展。尽管这些天然 Nrf2 激活剂的临床应用证据仍然有限，但我们相信，植物化学物质（如 Nrf2 激活剂）与基因和干细胞治疗的联合使用将是未来 TBI 的一种有前途的治疗策略。
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