Intracellular zinc is a critical intermediate in the excitotoxic cascade

Neurobiol Dis. 2015 Sep;81:25-37. doi: 10.1016/j.nbd.2015.04.010. Epub 2015 May 1.


Excessive and sustained exposure to glutamate leads to injurious elevations of cytosolic calcium ([Ca(2+)]i), generation of reactive oxygen and nitrogen species (ROS, RNS), mitochondrial failure, mobilization of intracellular zinc ([Zn(2+)]i), and, ultimately, neuronal death. The relative contribution and temporal dynamics of the activation of these processes to promote the full development of excitotoxicity are still not completely understood. In this study, we exploited the unique features of nNOS positive neurons [nNOS (+)], a striatal subpopulation that is constitutively spared from NMDAR-dependent insults, and dissected NMDAR-driven [Ca(2+)]i, [Zn(2+)]i, ROS, and mitochondrial changes occurring in these neurons and the overall population of nNOS (-) striatal neurons. Comparing the two populations and employing pharmacological, biochemical, and single-cell imaging techniques, we show that [Zn(2+)]i mobilization acts as a critical intermediate in the cascade that links NMDAR-mediated ROS overproduction, mitochondrial failure, and [Ca(2+)]i deregulation to the production of neuronal damage. Results of this study may also provide the rationale for aiming at therapeutic agents that favor Zn(2+) homeostasis for the treatment of acute or chronic neurological conditions associated with excitotoxicity.

Keywords: Calcium; Glutamate; Mitochondria; Neuronal death; Oxidative stress; nNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Corpus Striatum / cytology
  • Embryo, Mammalian
  • Excitatory Amino Acid Agonists / pharmacology*
  • Extracellular Fluid / drug effects*
  • Extracellular Fluid / metabolism
  • Glycine / pharmacology
  • L-Lactate Dehydrogenase (Cytochrome) / metabolism
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • N-Methylaspartate / pharmacology*
  • NADPH Dehydrogenase / metabolism
  • Neurons / cytology*
  • Neurons / drug effects
  • Nitric Oxide Synthase Type I / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Zinc / metabolism*


  • Excitatory Amino Acid Agonists
  • Reactive Oxygen Species
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • L-Lactate Dehydrogenase (Cytochrome)
  • Nitric Oxide Synthase Type I
  • NADPH Dehydrogenase
  • Zinc
  • Calcium
  • Glycine