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 Abeta 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.
Capasso
Margherita
M
Department of Neurology, CESI-Center for Excellence on Aging, University G. d'Annunzio, Chieti, 66013, Italy.
Jeng
Jade-Ming
JM
Malavolta
Marco
M
Mocchegiani
Eugenio
E
Sensi
Stefano L
SL
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D015032:Zinc