title: Neuroprotective effects of mebudipine and dibudipine on cerebral oxygen-glucose deprivation/reperfusion injury.
abstract: In the present study, we investigated the effects of mebudipine and dibudipine, two new Ca(2+) channel blockers, on primary murine cortical neurons exposed to oxygen-glucose deprivation/reperfusion. The experiments were performed on cells after 11-16 days of culture. To initiate oxygen-glucose deprivation /reperfusion, the culture medium was replaced by glucose-free medium, and the cells were transferred to a humidified incubation chamber in a mixture of 95% N(2) and 5% CO(2) at 37 degrees C for 30 min. The cultures were pretreated with mebudipine and dibudipine 3 h prior to oxygen-glucose deprivation/reperfusion, in order to explore their effects on neurons under oxygen-glucose deprivation conditions. Cell viability and nitric oxide (NO) production were assessed by MTT assay and the modified Griess method, respectively. Exposure of murine cortical neuronal cells to 30 min oxygen-glucose deprivation significantly decreased cell viability and increased NO production. Pretreatment of the cultures with mebudipine and dibudipine significantly increased cell viability and decreased NO generation in a dose-dependent manner. However, the drugs had no protective effect in cells subjected to oxygen-glucose deprivation for 60 min. Pretreatment of cultures with MK-801 (10 microM), a non-competitive NMDA antagonist, decreased neuronal death after 30-min oxygen-glucose deprivation, while application of NBQX (30 microM), a selective AMPA-kainate receptor antagonist, partially attenuated the cell injury. oxygen-glucose deprivation -induced cytotoxicity and NO production were also inhibited by N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor and MK-801. We conclude that mebudipine and dibudipine could protect cortical neurons against oxygen-glucose deprivation /reperfusion-induced cell injury in a dose-dependent manner, and that this could be mediated partially by decreased NO production.
authors.affiliation: Razi Institute For Drug Research, Department of Pharmacology, Iran University of Medical Science, Tehran, Iran.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Tavakoli-Far
authors.forename: Nahid
authors.initials: N
authors.lastname: Rahbar-Roshandel
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Rahimi-Moghaddam
authors.forename: Massoud
authors.initials: M
authors.lastname: Mahmoudian
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005562:Formazans / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000032:analysis; D011810:Quinoxalines / Q000494:pharmacology; D018092:Kainic Acid Receptors / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors
chemical_list: D016291:Dizocilpine Maleate; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005562:Formazans; D005947:Glucose; D016202:N-Methylaspartate; D019331:NG-Nitroarginine Methyl Ester; D018696:Neuroprotective Agents; D009543:Nifedipine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009573:Nitrites; D011810:Quinoxalines; D018092:Kainic Acid Receptors; D013778:Tetrazolium Salts; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C110813:dibudipine; C110812:mebudipine; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C079782:MTT formazan