Ischemic stroke is a major cause of death and disabilities worldwide, and it has been long hoped that improved understanding of relevant injury mechanisms would yield targeted neuroprotective therapies. While Ca²⁺ overload during ischemia-induced glutamate excitotoxicity has been identified as a major contributor, failures of glutamate targeted therapies to achieve desired clinical efficacy have dampened early hopes for the development of new treatments. However, additional studies examining possible contributions of Zn²⁺, a highly prevalent cation in the brain, have provided new insights that may help to rekindle the enthusiasm. In this review, we discuss both old and new findings yielding clues as to sources of the Zn²⁺ that accumulates in many forebrain neurons after ischemia, and mechanisms through which it mediates injury. Specifically, we highlight the growing evidence of important Zn²⁺ effects on mitochondria in promoting neuronal injury. A key focus has been to examine Zn²⁺ contributions to the degeneration of highly susceptible hippocampal pyramidal neurons. Recent studies provide evidence of differences in sources of Zn²⁺ and its interactions with mitochondria in CA1 versus CA3 neurons that may pertain to their differential vulnerabilities in disease. We propose that Zn²⁺-induced mitochondrial dysfunction is a critical and potentially targetable early event in the ischemic neuronal injury cascade, providing opportunities for the development of novel neuroprotective strategies to be delivered after transient ischemia.

缺血性中风是全世界死亡和残疾的主要原因，长期以来，人们一直希望对相关损伤机制的更好理解能够产生有针对性的神经保护疗法。虽然缺血诱导的谷氨酸兴奋性毒性过程中的 Ca ²⁺超载已被确定为主要贡献者，但谷氨酸靶向治疗未能达到预期的临床疗效已经削弱了开发新疗法的早期希望。然而，其他研究检查了大脑中高度普遍的阳离子 Zn ²⁺的可能贡献，提供了新的见解，可能有助于重新点燃热情。^{在这篇综述中，我们讨论了旧的和新的发现，为 Zn 2+}的来源提供了线索。它在缺血后在许多前脑神经元中积累，以及它介导损伤的机制。具体而言，我们强调了越来越多的证据表明 Zn ²⁺对线粒体促进神经元损伤有重要作用。一个重点是检查 Zn ²⁺对高度敏感的海马锥体神经元退化的贡献。最近的研究提供了 Zn ²⁺来源的差异及其与 CA1 和 CA3 神经元中线粒体相互作用的证据，这可能与它们在疾病中的不同脆弱性有关。我们建议 Zn ²⁺诱导的线粒体功能障碍是缺血性神经元损伤级联反应中的一个关键且潜在可靶向的早期事件，为开发在短暂性缺血后实施的新型神经保护策略提供了机会。