Nitric oxide-mediated effect of nipradilol, an alpha- and beta-adrenergic blocker, on glutamate neurotoxicity in rat cortical cultures.
Nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylamino)propoxy-3-nitroxy-2H-1-benzopyran) is used clinically as an anti-glaucoma ophthalmic solution in Japan, and was recently reported to suppress N-methyl-d-aspartate-induced retinal damage in rats. Here we investigated cytotoxic and cytoprotective actions of nipradilol on primary cultures of rat cortical neurons. Treatment of cortical cultures with a high concentration (500 microM) of nipradilol significantly reduced cell viability, increased lactate dehydrogenase (LDH) release and nitrite concentration in culture medium, whereas desnitro-nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylamino)propoxy-3-hydroxy-2H-1-benzopyran) had no significant effects. Nipradilol-induced neuronal damage was inhibited by S-hexylglutathione, a glutathione S-transferase inhibitor, and FeTPPS (5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride), a peroxynitrite decomposition catalyst. On the other hand, relatively low concentrations (10-100 microM) of nipradilol but not desnitro-nipradilol prevented neuronal cell death induced by 24 h application of 100 microM glutamate. Importantly, neuroprotective concentration (100 microM) of nipradilol suppressed glutamate-induced elevation of intracellular Ca2+ concentrations, but had no effect on intracellular cyclic GMP levels. Hence, nipradilol can protect cultured cortical neurons against glutamate neurotoxicity via cyclic GMP-independent mechanisms, and nitric oxide (NO) released from the nitoroxy moiety of nipradilol may mediate neuroprotective effect through the modulation of NMDA receptor function.
Taguchi
Ryota
R
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Shirakawa
Hisashi
H
Yamaguchi
Toshiaki
T
Kume
Toshiaki
T
Katsuki
Hiroshi
H
Akaike
Akinori
A
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011412:Propanolamines; D009569:Nitric Oxide; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C038539:3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-2H-1-benzopyran-3-ol; D007791:Lactoylglutathione Lyase; C036089:nipradilol; D005978:Glutathione; D006152:Cyclic GMP; C033550:hexylglutathione; D002118:Calcium