Liu Lei, Locascio Logan M, Doré Sylvain
Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida, Gainesville, FL, United States.
Departments of Neurology, Psychiatry, Pharmaceutics, and Neuroscience, University of Florida, Gainesville, FL, United States.
Front Pharmacol. 2019 Mar 5;10:153. doi: 10.3389/fphar.2019.00153. eCollection 2019.
Ischemic stroke is one of the leading causes of death and long-term disability worldwide; however, effective clinical approaches are still limited. The transcriptional factor Nrf2 is a master regulator in cellular and organismal defense against endogenous and exogenous stressors by coordinating basal and stress-inducible activation of multiple cytoprotective genes. The Nrf2 network not only tightly controls redox homeostasis but also regulates multiple intermediary metabolic processes. Therefore, targeting Nrf2 has emerged as an attractive therapeutic strategy for the prevention and treatment of CNS diseases including stroke. Here, the current understanding of the Nrf2 regulatory network is critically examined to present evidence for the contribution of Nrf2 pathway in rodent ischemic stroke models. This review outlines the literature for Nrf2 studies in preclinical stroke and focuses on the evidence for the role of Nrf2 in primary and secondary brain injuries. The dynamic change and functional importance of Nrf2 signaling, as well as Nrf2 targeted intervention, are revealed in permanent, transient, and global cerebral ischemia models. In addition, key considerations, pitfalls, and future potentials for Nrf2 studies in preclinical stroke investigation are discussed.
缺血性中风是全球范围内导致死亡和长期残疾的主要原因之一；然而，有效的临床治疗方法仍然有限。转录因子Nrf2通过协调多种细胞保护基因的基础激活和应激诱导激活，在细胞和机体抵御内源性和外源性应激源的过程中发挥着主要调节作用。Nrf2网络不仅严格控制氧化还原稳态，还调节多个中间代谢过程。因此，靶向Nrf2已成为预防和治疗包括中风在内的中枢神经系统疾病的一种有吸引力的治疗策略。在此，对目前对Nrf2调控网络的理解进行了批判性审视，以提供Nrf2通路在啮齿动物缺血性中风模型中的作用证据。本综述概述了临床前中风中Nrf2研究的文献，并重点关注Nrf2在原发性和继发性脑损伤中的作用证据。在永久性、短暂性和全脑缺血模型中揭示了Nrf2信号的动态变化和功能重要性，以及Nrf2靶向干预。此外，还讨论了临床前中风研究中Nrf2研究的关键考虑因素、陷阱和未来潜力。
