The neuroprotective effect of ONO-1714 on NMDA-mediated cytotoxicity in vitro.
We report the effects of a newly developed NOS inhibitor on the neurotoxicity induced by NMDA on cultured fetal rat cortical neurons. To date, three different isoforms of NOS have been characterized. It has been considered that both neuronal NOS and inducible NOS activities are detrimental to the ischemic brain, whereas endothelial NOS plays a prominent role in maintaining cerebral blood flow and prevents neuronal injury during ischemia. ONO-1714 is a newly developed competitive NOS inhibitor that has selective inhibitory potency for iNOS than eNOS. However, its effect on nNOS has not been investigated yet. In this study, we investigated the neuroprotective effect of ONO-1714 on NMDA-induced neurotoxicity in our established model of primary cultured cortical neurons of rat foetus. Cortical neurons (prepared from E16 rat foetuses) were used after 13-14 days in culture. The cells were exposed to 30 muM NMDA for 24 h in the culture. To evaluate the neuroprotective effects of NOS inhibitors, ONO-1714 and L-NAME, neurons were exposed to various concentrations of an NOS inhibitor with 30 muM NMDA. The NMDA induced neurotoxicity was significantly attenuated by ONO-1714 in all concentrations, but not in low to moderate concentrations of L-NAME. These findings demonstrate that the neuroprotective effect of ONO-1714 was more potent than L-NAME. Moreover, ONO-1714 has a strong inhibitory effect on nNOS and would be a powerful tool for the protection of neurons against cerebral ischemia.
Department of Anesthesiology and Acute Critical Medicine, Graduate School of Medicine, Osaka University (D7), 2-2 Yamadaoka, Osaka 565-0871, Suita, Japan. shibuta@anes.med.osaka-u.ac.jp
Satoshi
S
Shibuta
Sriranganathan
S
Varathan
Takashi
T
Mashimo
D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D006574:Heterocyclic Compounds, 2-Ring; D018696:Neuroprotective Agents; D016202:N-Methylaspartate