Brain zinc dyshomeostasis and glial cells in ischemic stroke

Abstract

Zinc, an essential trace element, plays an important role in a large number of biological functions. In mammalian brain, whereas the majority of brain zinc is bound to proteins including metallothionein, about 5–15% is stored in presynaptic vesicles of glutamatergic neurons throughout the forebrain, especially in the hippocampus, in a relatively free state. Thus, free zinc (Zn2+) concentration in the brain is considered to be regulated in order to maintain normal brain functions such as learning and memory. On the other hand, brain Zn2+ dyshomeostasis has been recognized as a mechanism for neuronal injury in brain disorders including Alzheimer’s disease and brain ischemia. In particular, after transient brain ischemia, Zn2+ accumulates in hippocampal neurons via a zinc transport system, or via release from cytosolic zinc-binding proteins, which results in neuronal cell death. Recently, it has been demonstrated that Zn2+ dyshomeostasis also occurs in glial cells such as microglia, astrocytes and oligodendrocytes after brain ischemia. In oligodendrocytes, ischemic insult triggers intracellular Zn2+ accumulation, resulting in cell death via mitochondrial dysfunction. Increased extracellular Zn2+ inhibits astrocytic glutamate uptake. In addition, extracellular Zn2+ massively released from ischemic neurons primes microglia to enhance production of pro-inflammatory cytokines in response to stimuli that trigger M1 activation. This review aims to describe the impact of brain Zn2+ dyshomeostasis on alterations in glial cell survival and functions in post-ischemic brains.