The role of zinc in cerebral ischemia

Abstract

Ischemic stroke is one of the most pervasive life-threatening neurological conditions for which there currently exists limited therapeutic intervention beyond prevention. As calcium-focused neuroprotective strategies have met with limited clinical success, it is imperative that alternative therapeutic targets be considered in the attempt to antagonize ischemic-mediated injury. As such, zinc, which is able to function both as a signaling mediator and neurotoxin, has been implicated in cerebral ischemia. While zinc was first purported to have a role in cerebral ischemia nearly twenty years ago, our understanding of how zinc mediates ischemic injury is still in its relative infancy. Within this review, we examine some of the studies by which zinc has exerted either neuroprotective or neurotoxic effects during global and focal cerebral ischemia.

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) (–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 (,,–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 (–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 GABA_A channels and inhibiting glutamate re-uptake by blocking excitatory amino acid transporters (EAAT-1) expressed on glial cells (–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) (–80). Zinc also can exert anti-apoptotic efforts through the inhibition of various caspases, pro-apoptotic genes, and endonucleases (–83).