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Neuronal preconditioning with the antianginal drug, Bepridil
Author(s) -
Gaspar Tamas,
Kis Bela,
Snipes James A,
Lenzser Gabor,
Mayanagi Keita,
Bari Ferenc,
Busija David W
Publication year - 2007
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.21.6.a1276
Subject(s) - pharmacology , superoxide dismutase , neuroprotection , glutathione peroxidase , chemistry , excitotoxicity , catalase , cardioprotection , reactive oxygen species , viability assay , glutathione , glutamate receptor , biochemistry , antioxidant , medicine , apoptosis , ischemia , enzyme , receptor
It has recently been shown that the antianginal drug Bepridil (BEP) activates mitochondrial ATP sensitive potassium (mitoK ATP ) channels and confers cardioprotection. Our aim was to investigate whether BEP could induce preconditioning in cultured rat cortical neurons. Although BEP depolarized mitochondria and increased free radical 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 μM, 59.6±1.53%∗; BEP 2.5 μM, 71.9±1.23%∗; BEP 5 μM, 95.3±0.89%∗; mean ± SEM; ∗p<0.001 vs. untreated) and 60 min of glutamate excitotoxicity (200 μM; cell viability: untreated, 54.1±0.69%; BEP 1 μM, 61.2±1.19%∗; BEP 2.5 μM, 78.1±1.67%∗; BEP 5 μM, 91.2±1.20%∗; mean ± SEM; ∗p<0.001 vs. untreated). The protection was antagonized with the superoxide dismutase mimetic M40401, but not with glutathione, catalase, or the mitoK ATP blocker 5‐hydroxydecanoate. BEP treatment resulted in increased levels and activity of protein kinase C, manganese‐dependent superoxide dismutase, catalase, 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. Supported by NIH grants (HL‐50587, HL‐65380, and HL‐77731) for D. W. Busija.