Affiliations: [a] Department of Neurology, CESI-Center for Excellence on Aging, University G. d'Annunzio, Chieti, 66013, Italy | [b] Department of Neurology, University of California, Irvine. CA 92697-4292, USA | [c] Department of Neurobiology & Behavior, University of California, Irvine. CA 92697-4550, USA | [d] Immunology Center (Section: Nutrition, Immunity and Ageing) Res. Department INRCA, via Birarelli 8, 60121, Ancona, Italy
Abstract: 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.
