Exacerbated responses to oxidative stress by an Na+ load in isolated nerve terminals: The role of ATP depletion and rise of [Ca2+](i)

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We have explored the consequences of a [Na+](i) load and oxidative stress in isolated nerve terminals. The Na+ load was achieved by veratridine (5-40 μM), which allows Na+ entry via a voltage-operated Na+ channel, and oxidative stress was induced by hydrogen peroxide (0.1-0.5 mM). Remarkably, neither the [Na+](i) load nor exposure to H2O2 had any major effect on [Ca2+](i), mitochondrial membrane potential (Δψm), or ATP level. However, the combination of an Na+ load and oxidative stress caused ATP depletion, a collapse of Δψm, and a progressive deregulation of [Ca2+](i) and [Na+](i) homeostasis. The decrease in the ATP level was unrelated to an increase in [Ca2+](i) and paralleled the rise in [Na+](i). The loss of Δψm was prevented in the absence of Ca2+ but unaltered in the presence of cyclosporin A. We conclude that the increased ATP consumption by the Na,K- ATPase that results from a modest [Na+](i) load places an additional demand on mitochondria metabolically compromised by an oxidative stress, which are unable to produce a sufficient amount of ATP to fuel the ATP-driven ion pumps. This results in a deregulation of [Na+](i) and [Ca2+](i), and as a result of the latter, collapse of Δψm. The vicious cycle generated in the combined presence of Na+ load and oxidative stress could be an important factor in the neuronal injury produced by ischemia or excitotoxicity, in which the oxidative insult is superimposed on a disturbed Na+ homeostasis.

Original languageEnglish
Pages (from-to)2094-2103
Number of pages10
JournalJournal of Neuroscience
Issue number6
Publication statusPublished - Mar 15 2000


  • ATP depletion
  • Mitochondrial membrane potential
  • Na deregulation; Ca deregulation
  • Na load
  • Oxidative stress

ASJC Scopus subject areas

  • Neuroscience(all)

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