Nitric oxide-mediated effect of nipradilol, an alpha- and beta-adrenergic blocker, on glutamate neurotoxicity in rat cortical cultures.

Abstract

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.

• Authors: Ryota Taguchi, Hisashi Shirakawa, Toshiaki Yamaguchi, Toshiaki Kume, Hiroshi Katsuki, Akinori Akaike
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 535 Issue 1-3 Pg. 86-94 (Mar 27 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16516884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-Antagonists
• Adrenergic beta-Antagonists
• Enzyme Inhibitors
• Neuroprotective Agents
• Propanolamines
• Nitric Oxide
• Glutamic Acid
• Dizocilpine Maleate
• 3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-2H-1-benzopyran-3-ol
• Lactoylglutathione Lyase
• nipradilol
• Glutathione
• Cyclic GMP
• hexylglutathione
• Calcium

Topics

• Adrenergic alpha-Antagonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Calcium (metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Cerebral Cortex
• Cyclic GMP (metabolism)
• Dizocilpine Maleate (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Fetus
• Glutamic Acid (toxicity)
• Glutathione (analogs & derivatives, pharmacology)
• Lactoylglutathione Lyase (antagonists & inhibitors)
• Neurons (cytology, drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (metabolism)
• Pregnancy
• Propanolamines (pharmacology)
• Rats
• Rats, Wistar