Trends in Pharmacological Sciences
ReviewZinc: new clues to diverse roles in brain ischemia
Section snippets
Zinc ions (Zn2+) in the nervous system
Zn2+ is an essential cofactor for many enzymes and transcription factors. Its levels in all cells are tightly regulated by the combined actions of transporter proteins, channels and intracellular binding proteins. Additionally, it appears to have roles in neuronal synaptic transmission because high concentrations of Zn2+ are accumulated in many synaptic vesicles within the central nervous system (CNS) (due to the activity of the selective Zn2+ transporter ZnT3 [1]) and there is evidence for its
Influx from the extracellular space
In recent years, microdialysis studies have confirmed accumulation of extracellular Zn2+ in focal and global ischemia models 8, 9. Understanding the sources of accumulation of extracellular Zn2+ could be valuable for targeting Zn2+ in ischemia. In future studies, it will be useful to test for synaptic vs other sources of ischemic Zn2+ accumulations using animals that lack the vesicular Zn2+ tranaporter ZnT3. These animals are viable, lack synaptic Zn2+ within the CNS, and have been used to
Relationship between Ca2+ and Zn2+ in the induction of ischemic neurodegeneration
There has been considerable discussion of the relative contributions of Zn2+ and Ca2+ to ischemic injury, resulting in part from the sensitivity of Ca2+ indicators to Zn2+ (Box 1). However, recent studies simultaneously tracking changes in these two ions suggest that they each contribute distinct and important effects to neuronal injury.
Recent work suggests that aberrant Zn2+ accumulation can serve as an upstream contributor to deregulation of Ca2+ to toxic levels within neurons. In studies of
Multiple and potent effects of Zn2+ on mitochondrial function
In 2000, we highlighted emerging clues to the potent effects of Zn2+ on mitochondrial function, which probably has relevance to ischemia. Insights over the past decade have made it progressively clear that Zn2+–mitochondrial interactions occur in, and appear to contribute to, ischemic injury.
Pathological Zn2+ accumulation can affect mitochondrial function in various ways. Zn2+ induces swelling and release of reactive oxygen species (ROS) from mitochondria in isolation or in cultured neurons 5,
Mitogen-activated protein (MAP) kinases and transcriptional regulation in Zn2+-dependent neurodegeneration
It is increasingly clear that Zn2+ has powerful effects on a multitude of cell signaling cascades. These effects are complex and, depending upon conditions, the net result may be protective or injurious. Several studies suggest that Zn2+ can mediate neuronal injury via activation of members of the MAP kinase family, particularly P38 and extracellular signal-regulated kinases (ERK). MAP kinases have crucial roles in the regulation of the survival, proliferation and death of cells, and are
Concluding remarks
The above discussions highlight new insights, largely from the past decade, into ways in which Zn2+ may contribute to different stages and components of the ischemic injury cascade (Figure 2). Although still a relatively new research area, the picture is coming into sharper focus, with clear evidence for the distinct roles of Zn2+ at different sites of action and probably different timeframes after ischemic insults.
With brief sublethal ischemia, extracellular Zn2+ accumulation may be protective
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