Rethinking the excitotoxic ionic milieu:: The emerging role of Zn2+ in ischemic neuronal injury

Zn2+ plays an important role in diverse physiological processes, but when released in excess amounts it is potently neurotoxic. In vivo trans-synaptic movement and subsequent post-synaptic accumulation of intracellular Zn2+ contributes to the neuronal injury observed in SOME forms of cerebral ischemia. Zn2+ may enter neurons through NMDA channels, voltage-sensitive calcium channels, Ca2+-permeable AMPA/kainate (Ca-A/K) channels, or Zn2+-sensitive membrane transporters. Furthermore, Zn2+ is also released from intracellular sites such as metallothioneins and mitochondria. The mechanisms by which Zn2+ exerts its potent neurotoxic effects involve many signaling pathways, including mitochondrial and extra-mitochondrial generation of reactive oxygen species (ROS) and disruption of metabolic enzyme activity, ultimately leading to activation of apoptotic and/or necrotic processes. As is the case with Ca2+, neuronal mitochondria take up Zn2+ as a way of modulating cellular Zn2+ homeostasis. However, excessive mitochondrial Zn2+ sequestration leads to a marked dysfunction of these organelles, characterized by prolonged ROS generation. Intriguingly, in direct comparison to Ca2+, Zn2+ appears to induce these changes with a considerably greater degree of potency. These effects are particularly evident upon large (i.e., micromolar) rises in intracellular Zn2+ concentration ([Zn2+](i)), and likely hasten necrotic neuronal death. In contrast, sub-micromolar [Zn2+](i) increases promote release of pro-apoptotic factors, suggesting that different intensities of [Zn2+](i) load may activate distinct pathways of injury. Finally, Zn2+ homeostasis seems particularly sensitive to the environmental changes observed in ischemia, such as acidosis and oxidative stress, indicating that alterations in [Zn2+](i) may play a very significant role in the development of ischemic neuronal damage.