Zinc dyshomeostasis: A key modulator of neuronal injury

Zn²⁺ is a potently toxic cation involved in the neuronal injury observed in cerebral ischemia, epilepsy, and brain trauma. Toxic Zn²⁺ accumulation may result from either trans-synaptic Zn²⁺ movement and/or cation mobilization from intracellular sites. To gain entry to the cytosol, Zn²⁺ can flux through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn²⁺-sensitive membrane transporters, while metallothioneins and mitochondria provide sites of intracellular Zn²⁺ release. Intracellular Zn²⁺ homeostasis is sensitive to patho-physiological environmental changes, such as acidosis, inflammation and oxidative stress. The mechanisms by which Zn²⁺ exerts its neurotoxicity include mitochondrial and extra-mitochondrial production of reactive oxygen species and disruption of metabolic enzymatic activity, ultimately leading to activation of apoptotic and/or necrotic processes. Beside acute neuronal injury, an exciting new area of investigation is offered by the role of Zn²⁺ dysmetabolism in Alzheimer's disease as the cation acts as a potent trigger for Aβ aggregation and plaque formation. Finally, recent findings suggest that alteration of Zn²⁺ homeostasis might also be a critical contributor to aging-related neurodegenerative processes. Thus, multiple evidence suggest that modulation of intracellular and extracellular Zn²⁺ might be an important therapeutical target for the treatment of a vast array of neurological conditions ranging from stroke to Alzheimer's disease.