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Delayed preconditioning with NS1619 protects cultured cortical neurons against both apoptotic and necrotic cell deaths
Author(s) -
Gaspar Tamas,
Katakam Prasad VG,
Domoki Ferenc,
Snipes James A,
Kis Bela,
Bari Ferenc,
Busija David W
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.733.8
Subject(s) - chemistry , activator (genetics) , reactive oxygen species , neuroprotection , antagonist , microbiology and biotechnology , bk channel , pharmacology , membrane potential , biophysics , receptor , biochemistry , biology
NS1619, a potent activator of the large conductance Ca 2+ activated potassium (BK Ca ) channel, has been demonstrated to induce preconditioning in the heart. The aim of our study was to test the delayed preconditioning 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. In addition, 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 blocked by a superoxide dismutase mimetic and a PI3K antagonist, but not by BK Ca channel inhibitors. Furthermore, NS1619 increased ROS generation, depolarized isolated mitochondria, hyperpolarized the neuronal cell membrane, and activated the PI3K signaling cascade. Finally, NS1619 inhibited the activation of capase‐3/7. In summary, NS1619 is a potent inducer of delayed neuronal preconditioning. 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. Supported by the NIH Grants HL‐030260, HL‐065380, and HL‐077731.