Neuronal preconditioning with the antianginal drug, bepridil

• Published in: Journal of neurochemistry Vol. 102; no. 3; pp. 595 - 608
• Main Authors: Gáspár, Tamás, Kis, Béla, Snipes, James A, Lenzsér, Gábor, Mayanagi, Keita, Bari, Ferenc, Busija, David W
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.08.2007; Blackwell Publishing Ltd; Blackwell
• Subjects: Ageing, cell death; Analysis; Animals; Bcl-2; Bepridil - pharmacology; Bepridil - therapeutic use; Biological and medical sciences; Brain - blood supply; Brain - drug effects; Brain - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Cell physiology; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Cellular biology; Cerebral Cortex - blood supply; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; General pharmacology; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - physiopathology; Ischemic Preconditioning - methods; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; mitochondria; Molecular and cellular biology; Molecular biology; neuronal culture; Neurons; Neurons - drug effects; Neurons - metabolism; neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Neurotransmitters; Organometallic Compounds - pharmacology; Pharmacology. Drug treatments; protein kinase C; Protein Kinase C - drug effects; Protein Kinase C - metabolism; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; reactive oxygen species; Reactive Oxygen Species - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Superoxide Dismutase - drug effects; Superoxide Dismutase - metabolism; Drug; Bcl-2; Oxygen; Deprivation; Rat; Bcl-2 protein; Acute; Rodentia; Ionic channel; Glucose; Vertebrata; Mitochondria; Mammalia; Neuron; Treatment; neuroprotection; reactive oxygen species; Excitatory aminoacid; Neurotransmitter; neuronal culture; ATP; Potassium; Preconditioning; protein kinase C
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04501.x

It has recently been shown that the antianginal drug bepridil (BEP) activates mitochondrial ATP-sensitive potassium (mitoKATP) 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 μmol/L, 59.6 ± 1.53%*; BEP 2.5 μmol/L, 71.9 ± 1.23%*; BEP 5 μmol/L, 95.3 ± 0.89%*; mean ± SEM; *p < 0.05 vs. untreated) and 60 min of glutamate excitotoxicity (200 μmol/L; cell viability: untreated, 54.1 ± 0.69%; BEP 1 μmol/L, 61.2 ± 1.19%*; BEP 2.5 μmol/L, 78.1 ± 1.67%*; BEP 5 μmol/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 mitoKATP 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 mitoKATP activation.