title: Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channels.
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 (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, 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 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.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina, USA. gaspar@wfubmc.edu
authors.forename: Tamás
authors.initials: T
authors.lastname: Gáspár
authors.forename: Prasad
authors.initials: P
authors.lastname: Katakam
authors.forename: James A
authors.initials: JA
authors.lastname: Snipes
authors.forename: Béla
authors.initials: B
authors.lastname: Kis
authors.forename: Ferenc
authors.initials: F
authors.lastname: Domoki
authors.forename: Ferenc
authors.initials: F
authors.lastname: Bari
authors.forename: David W
authors.initials: DW
authors.lastname: Busija
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D024681:Potassium Channels, Calcium-Activated; C086491:NS 1619