Figure 1
Schematic Overview of the Putative Toxic and Protective Mechanisms Elicited by Zinc during Cerebral Ischemia
During ischemia, heightened release of zinc from a subset of glutamatergic terminals likely promotes the translocation and accumulation of zinc in vulnerable post-synaptic neurons. Following release, synaptic zinc is thought to achieve cellular access predominately through subpopulations of calcium-permeable AMPA and/or kainate channels (Ca-A/K) (56–58). Zinc entry may also be facilitated by the zinc-sodium exchanger and less predominately through voltage sensitive calcium channels (VSCC) or NMDA-type glutamate receptors (56,57,59,60). Intense cytosolic zinc overloads, likely mediated by Ca-A/K receptor channels, can promote pronounced mitochondrial dysfunction and reactive oxygen species (ROS) generation to trigger necrosis, whereas milder cytosolic zinc loads may augment apoptotic pathways (43,57,61–63). The cellular oxidative stress and acidosis achieved during ischemia may additionally promote the liberation of zinc from zinc-ligands, such as metallothioneins (39,49,64,65). In the attempt to confer resistance to the rising cytosolic zinc levels, the zinc transporter, ZnT-1 and metallothionien III can be upregulated during ischemia to promote zinc efflux and cytosolic buffering, respectively (12,66,67). Zinc also plays an integral role in the subunit expression of Ca-A/K channels during ischemia by altering transcriptional regulation that leads to GluR2 subunit downregulation, the presence of which renders A/K receptor channels calcium-impermeable (20–23). Zinc also can activate signal transduction pathways, such as protein kinase C, which can promote ROS generation (68,69). Zinc also can augment glutamate-induced neuronal injury by directly inhibiting GABAA channels and inhibiting glutamate re-uptake by blocking excitatory amino acid transporters (EAAT-1) expressed on glial cells (70–72). During ischemia, activation of Ca-A/K receptor channels, acidosis, and elevated zinc levels can also work synergistically to promote glial injury (73). Conversely, during ischemia, zinc also may achieve protective effects by substantially inhibiting calcium influx by blocking NMDA-type glutamate receptor channels or acid-sensing ion channels (ASICs) (74–80). Zinc also can exert anti-apoptotic efforts through the inhibition of various caspases, pro-apoptotic genes, and endonucleases (81–83).