Neuronal preconditioning with the antianginal drug, bepridil.
It has recently been shown that the antianginal drug bepridil (BEP) activates mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels and thus confers cardioprotection. Our aim was to investigate whether BEP could induce preconditioning in cultured rat cortical neurons. Although BEP depolarized isolated and in situ mitochondria and increased reactive oxygen species generation, no acute protection was observed. However, a 3-day BEP-treatment elicited dose-dependent delayed neuroprotection against 180 min of oxygen-glucose deprivation (cell viability: untreated, 52.5 +/- 0.85%; BEP 1 micromol/L, 59.6 +/- 1.53%*; BEP 2.5 micromol/L, 71.9 +/- 1.23%*; BEP 5 micromol/L, 95.3 +/- 0.89%*; mean +/- SEM; *p < 0.05 vs. untreated) and 60 min of glutamate excitotoxicity (200 micromol/L; cell viability: untreated, 54.1 +/- 0.69%; BEP 1 micromol/L, 61.2 +/- 1.19%*; BEP 2.5 micromol/L, 78.1 +/- 1.67%*; BEP 5 micromol/L, 91.2 +/- 1.20%*; mean +/- SEM; *p < 0.05 vs. untreated), and inhibited the reactive oxygen species surge upon glutamate exposure. The protection was antagonized with co-application of the superoxide dismutase mimetic M40401, but not with reduced glutathione, catalase, or with the mitoK(ATP) blocker 5-hydroxydecanoate. Furthermore, BEP treatment resulted in increased levels of phosphorylated protein kinase C, manganese-dependent superoxide dismutase, glutathione peroxidase, and Bcl-2. Our results indicate that BEP induces delayed neuronal preconditioning which is dependent on superoxide generation but perhaps not on direct mitoK(ATP) activation.
Gáspár
Tamás
T
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157-1010, USA. tgaspar@wfubmc.edu
Kis
Béla
B
Snipes
James A
JA
Lenzsér
Gábor
G
Mayanagi
Keita
K
Bari
Ferenc
F
Busija
David W
DW
D000818:Animals; D015764:Bepridil / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019194:Ischemic Preconditioning / Q000379:methods*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; C426066:M40401; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D015764:Bepridil; D013482:Superoxide Dismutase; D011493:Protein Kinase C