The mitochondrial K(ATP) channel opener BMS-191095 induces neuronal preconditioning.
BMS-191095, reportedly a selective mitoK(ATP) channel opener which is free from the known side effects of the prototype mitoK(ATP) channel opener diazoxide, induced acute and delayed preconditioning against glutamate excitotoxicity and delayed preconditioning against oxygen-glucose deprivation in primary cultures of rat cortical neurons. BMS-191095 dose dependently depolarized the mitochondria, increased the phosphorylation of PKC isoforms, but had no detectable effects on the activation of MAP kinases and did not influence the expressions of HSP70 and Mn-SOD. In BMS-191095-preconditioned neurons the glutamate-induced free-radical production was abolished. Our data give the first evidence that selective opening of mitoK(ATP) channels with BMS-191095 leads to remarkable neuroprotection via mechanisms that involve mitochondrial depolarization, PKC activation and attenuated free radical production during neuronal stress.
Kis
Bela
B
Department of Physiology and Pharmacology, Wake Forest University, School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. bkis@wfubmc.edu
Nagy
Krisztina
K
Snipes
James A
JA
Rajapakse
Nishadi C
NC
Horiguchi
Takashi
T
Grover
Gary J
GJ
Busija
David W
DW
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D019194:Ischemic Preconditioning / Q000379:methods*; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C428117:BMS 191095; D001578:Benzopyrans; D005609:Free Radicals; D007093:Imidazoles; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D011493:Protein Kinase C; D005947:Glucose