Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels

Tamás Gáspár, Prasad Katakam, James A. Snipes, Béla Kis, Ferenc Domoki, Ferenc Bari, David W. Busija

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl) -2H-benzimidazol-2-one (NS1619), a potent activator of the large conductance Ca2+ activated potassium (BKCa) channel, has been demonstrated to induce preconditioning (PC) in the heart. The aim of our study was to test the delayed PC effect of NS1619 in rat cortical neuronal cultures against oxygen-glucose deprivation, H2O2, or glutamate excitotoxicity. We also investigated its actions on reactive oxygen species (ROS) generation, and on mitochondrial and plasma membrane potentials. Furthermore, we tested the activation of the phosphoinositide 3-kinase (PI3K) signaling pathway, and the effect of NS1619 on caspase-3/7. NS1619 dose-dependently protected the cells against the toxic insults, and the protection was completely blocked by a superoxide dismutase mimetic and a PI3K antagonist, but not by BKCa channel inhibitors. Application of NS1619 increased ROS generation, depolarized isolated mitochondria, hyperpolarized the neuronal cell membrane, and activated the PI3K signaling cascade. However, only the effect on the cell membrane potential was antagonized by BKCa channel blockers. NS1619 inhibited the activation of capase-3/7. In summary, NS1619 is a potent inducer of delayed neuronal PC. However, the neuroprotective effect seems to be independent of cell membrane and mitochondrial BK Ca channels. Rather it is the consequence of ROS generation, activation of the PI3K pathway, and inhibition of caspase activation.

Original languageEnglish
Pages (from-to)1115-1128
Number of pages14
JournalJournal of neurochemistry
Volume105
Issue number4
DOIs
Publication statusPublished - May 2008

Keywords

  • BK channel
  • Mitochondria
  • Neuronal culture
  • Neuroprotection
  • Phosphoinositide 3-kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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