Much attention has been paid to the possibility that excessive calcium influx may contribute to neuronal death after ischemic insults. This proposal will turn a spotlight on an alternative divalent cation messenger mediating ischemic cell death, Zn2+. Several in vitro studies show that even brief exposure to Zn2+ can kill cultured cortical neurons, and in vivo studies suggests that Zn2+ influx may contribute to selective neuronal cell loss after transient global ischemia. The hypothesis will be tested that the toxic translocation of synaptic Zn2+ from presynaptic terminals into postsynaptic cells contributes to the development of infarction following focal ischemia.
Three Aims are proposed.
The first Aim sets out to demonstrate that synaptic Zn2+ translocates into neurons and astrocytes after focal ischemia and follows a timecourse that defines the therapeutic window for extracellular Zn2+ chelation.
The second Aim will take advantage of different methods for manipulating presynaptic Zn2+ content to determine if these manipulation will affect Zn2+ translocation and injury following focal ischemia.
The third Aim will focus on the influence of postsynaptic Zn2+ homeostasis on vulnerability to infarction following ischemia. Experiments in this proposal are intended to lead to an enhanced understanding of the newly identified contribution of Zn2+ toxicity to ischemic brain damage, and thus aid the future development of effective clinical therapeutic strategies for the treatment of acute ischemic stroke.
