- Cerebral ischemia is a leading cause of morbidity and mortality, reflecting the extraordinary sensitivity of the brain to a brief loss of blood flow. A significant goal has been to identify pathways of neuronal injury that are selectively activated after stroke and may be amenable to drug therapy. An important advance was made nearly 25 years ago when Ca(2+) overload was implicated as a critical link between glutamate excitotoxicity and ischemic neurodegeneration. However, early hope for effective therapies faded as glutamate-targeted trials repeatedly failed to demonstrate efficacy in humans. In a review in 2000 in this journal, we described new evidence linking a related cation, zinc (Zn(2+)), to neuronal injury, emphasizing sources and mechanisms of Zn(2+) toxicity. The current review highlights progress over the last decade, emphasizing mechanisms through which Zn(2+) ions (from multiple sources) participate together with Ca(2+) in different stages of cascades of ischemic injury.Copyright © 2011 Elsevier Ltd. All rights reserved.