Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
Beijing Geriatric Medical Research Center, Beijing 100053, China.
Metallomics. 2024 Mar 12;16(3). doi: 10.1093/mtomcs/mfae012.
Ischemic stroke is a leading cause of death and disability worldwide, and presently, there is no effective neuroprotective therapy. Zinc is an essential trace element that plays important physiological roles in the central nervous system. Free zinc concentration is tightly regulated by zinc-related proteins in the brain under normal conditions. Disruption of zinc homeostasis, however, has been found to play an important role in the mechanism of brain injury following ischemic stroke. A large of free zinc releases from storage sites after cerebral ischemia, which affects the functions and survival of nerve cells, including neurons, astrocytes, and microglia, resulting in cell death. Ischemia-triggered intracellular zinc accumulation also disrupts the function of blood-brain barrier via increasing its permeability, impairing endothelial cell function, and altering tight junction levels. Oxidative stress and neuroinflammation have been reported to be as major pathological mechanisms in cerebral ischemia/reperfusion injury. Studies have showed that the accumulation of intracellular free zinc could impair mitochondrial function to result in oxidative stress, and form a positive feedback loop between zinc accumulation and reactive oxygen species production, which leads to a series of harmful reactions. Meanwhile, elevated intracellular zinc leads to neuroinflammation. Recent studies also showed that autophagy is one of the important mechanisms of zinc toxicity after ischemic injury. Interrupting the accumulation of zinc will reduce cerebral ischemia injury and improve neurological outcomes. This review summarizes the role of zinc toxicity in cellular and tissue damage following cerebral ischemia, focusing on the mechanisms about oxidative stress, inflammation, and autophagy.
缺血性脑卒中是全球范围内主要的致死和致残原因，目前尚无有效的神经保护治疗方法。锌是一种必需的微量元素，在中枢神经系统中发挥着重要的生理作用。在正常情况下，大脑中的锌相关蛋白会对游离锌浓度进行严格的调节。然而，锌稳态的破坏已被发现与缺血性脑卒中后脑损伤的机制有关。脑缺血后，大量的游离锌从储存部位释放出来，影响神经元、星形胶质细胞和小胶质细胞等神经细胞的功能和存活，导致细胞死亡。缺血触发的细胞内锌积累也会通过增加其通透性、损害内皮细胞功能和改变紧密连接水平来破坏血脑屏障的功能。氧化应激和神经炎症已被报道为脑缺血/再灌注损伤的主要病理机制。研究表明，细胞内游离锌的积累会损害线粒体功能，导致氧化应激，并在锌积累和活性氧产生之间形成正反馈循环，导致一系列有害反应。同时，细胞内锌水平升高会导致神经炎症。最近的研究还表明，自噬是缺血性损伤后锌毒性的重要机制之一。阻断锌的积累将减轻脑缺血损伤并改善神经功能结局。本综述总结了锌毒性在脑缺血后细胞和组织损伤中的作用，重点讨论了氧化应激、炎症和自噬的相关机制。
