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Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels
Author(s) -
Gáspár Tamás,
Katakam Prasad,
Snipes James A.,
Kis Béla,
Domoki Ferenc,
Bari Ferenc,
Busija David W.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05210.x
Subject(s) - chemistry , bk channel , activator (genetics) , potassium channel , reactive oxygen species , calcium activated potassium channel , biophysics , antagonist , neuroprotection , membrane potential , mitochondrion , pharmacology , microbiology and biotechnology , biochemistry , receptor , biology
1,3‐Dihydro‐1‐[2‐hydroxy‐5‐(trifluoromethyl)phenyl]‐5‐(trifluoromethyl)‐2H‐benzimidazol‐2‐one (NS1619), a potent activator of the large conductance Ca 2+ activated potassium (BK Ca ) 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, H 2 O 2 , 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 BK Ca 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 BK Ca 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.