Pathophysiological role of zinc in ischemic brain injury

Zinc is the second most abundant metal in human body, and a relatively large amount of zinc is found in the brain, indicating its essential role in central nerve system. Zn 2+ is stored in synaptic vesicles of glutamatergic neurons and is released from the terminals for synaptic signaling. Zinc is also found in zinc containing proteins. It is estimated that the human proteome contains about 3000 zinc-containing proteins serving signaling, catalytic, and structural roles. In zinc-finger proteins, for example, a zinc ion is complexed in a zinc finger motif through four invariant cysteine and/or histidine residues to form a stable structure and conformation, which regulates protein-DNA, protein-RNA, and protein-protein interactions [1]. Twenty years ago, abnormal zinc accumulation was first observed in ischemic neurons, which leads to neuronal injuries after cerebral ischemia [2]. We recently reported that intracellular zinc dramatically elevated in neurons in the first a few hours following cerebral ischemia, resulting in neuronal apoptotic death in a rat stroke model [3]. We also found that zinc overload contributed to mitochondrial dysfunction in ischemic neurons [4]. Removing zinc with a specific zinc chelator (TPEN) reduced zinc accumulation in ischemic neurons and rescued them from cell death [3, 4]. These findings implicate zinc as a potential target to block the cascade of events leading to ischemic injury. Zinc release from ischemic neurons to extracellular matrix could produce a surrounding environment with a high concentration of zinc after cerebral ischemia. Strong activities of zinc-containing presynaptic terminals may transiently increase local synaptic zinc concentrations up to 300µM, making it available for entry or uptake by neighboring cells [5]. Microdialysis studies confirmed the increase of extracellular zinc in cerebral ischemia models. Our unpublished data showed that reducing zinc in extracellular matrix with a membrane-impermeable zinc chelator, CaEDTA, could reduce ischemia-induced microvessel injury. These findings suggest that extracellular zinc may be a critical mediator of ischemic brain insult. Astrocytes can take up the excessive extracellular zinc from synaptic cleft or extracellular matrix to maintain zinc homeostasis. However, zinc overload in astrocytes may induce astrocytic cell death. Our study indicated that zinc overload under hypoxic condition caused a dramatic increase in astrocytic cell death in a zinc-concentration-dependent manner [6]. Very interestingly, hypoxia/ reoxygenation markedly decreased zinc transporter ZnT-1 expression to reduce zinc efflux. Together, these results suggest that hypoxia/reoxygenation may impede the zinc efflux from cells, providing a novel mechanism for intracellular free zinc accumulation …