Rethinking the Excitotoxic Ionic Milieu:The Emerging Role of Zn 2+ in Ischemic Neuronal Injury

S.   L.   Sensi; J.-   M.   Jeng

doi:10.2174/1566524043479211

Abstract

Zn 2+plays an important role in diverse physiological processes,but when released in excess amounts it is potently neurotoxic.In vivo trans-synaptic movement and subsequent post-synaptic accumulation of intracellular Zn 2+contributes to the neuronal injury observed in some forms of cerebral ischemia.Zn 2+may enter neurons through NMDA channels,voltage-sensitive calcium channels,Ca 2+- permeable AMPA / kainate (Ca-A / K)channels,or Zn 2+-sensitive membrane transporters.Furthermore, Zn 2+is also released from intracellular sites such as metallothioneins and mitochondria.The mechanisms by which Zn 2+exerts its potent neurotoxic effects involve many signaling pathways, including mitochondrial and extra-mitochondrial generation of reactive oxygen species (ROS)and disruption of metabolic enzyme activity,ultimately leading to activation of apoptotic and / or necrotic processes. As is the case with Ca 2+,neuronal mitochondria take up Zn 2+as a way of modulating cellular Zn 2+ homeostasis.However,excessive mitochondrial Zn 2+sequestration leads to a marked dysfunction of these organelles,characterized by prolonged ROS generation.Intriguingly,in direct comparison to Ca 2+,Zn 2+appears to induce these changes with a considerably greater degree of potency.These effects are particularly evident upon large (i.e.,micromolar)rises in intracellular Zn 2+concentration ([Zn 2+]i ),and likely hasten necrotic neuronal death.In contrast,sub-micromolar [Zn 2+]i increases promote release of pro-apoptotic factors,suggesting that different intensities of [Zn 2+]i load may activate distinct pathways of injury.Finally,Zn 2+homeostasis seems particularly sensitive to the environmental changes observed in ischemia,such as acidosis and oxidative stress,indicating that alterations in [Zn 2+]i may play a very significant role in the development of ischemic neuronal damage.

Keywords: Ionic Milieu, micromolar, ischemia

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