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Ketamine and thiopental sodium: individual and combined neuroprotective effects on cortical cultures exposed to NMDA or nitric oxide

2006; Elsevier BV; Volume: 97; Issue: 4 Linguagem: Inglês

10.1093/bja/ael192

1471-6771

Satoshi Shibuta, Sriranganathan Varathan, Takashi Mashimo,

Treatment of Major Depression

BackgroundAn N-methyl-d-aspartate (NMDA) blocker, ketamine, has been shown to be neuroprotective both in vivo and in vitro. However, ketamine is not commonly recommended for use in patients suffering from cerebral ischaemia because of its adverse neurological effects. We hypothesized that combined administration of ketamine and thiopental sodium (TPS) would be highly effective in protecting cerebral cortical neurones from ischaemia, with possibly reduced dosages.MethodsWe examined the degree of neuroprotection provided by various concentrations of ketamine and TPS, alone and in combination, in cortical cultures exposed to NMDA or a nitric oxide-releasing compound (NOC-5) for 24 h. The survival rate (SR) of E16 Wistar rat cortical neurones was evaluated using photomicrographs before and after exposure to these compounds.ResultsThe SRs of cortical neurones exposed to 30 μM NMDA or NOC-5 were 15.0 (3.8)%, 12.8 (3.1)%, respectively. Higher doses (5, 10 and 50 μM) but not lower doses (<1 μM) of ketamine improved SRs [57.9 (2.2)%, 61.1 (5.4)%, 76.7 (3.0)%, respectively] against NMDA but not NOC. Enhanced survival was observed with combined administration of 5 or 10 μM ketamine and 50 μM TPS [SR 71.3 (4.8)%, 74.7 (3.7)%, respectively, P<0.05 if ketamine alone, P<0.01 if TPS alone], against NMDA-induced neurotoxicity in vitro. Only the highest dose of TPS (50 μM) improved survival after NOC exposure. This neuroprotection was not influenced by ketamine.ConclusionsThese data indicate that a low, clinically relevant dose of ketamine offer significant neuroprotection during prolonged exposure to NMDA but not to NOC. Combinations of reduced doses of ketamine and TPS exhibited enhanced neuroprotection against NMDA-induced neurotoxicity. Hence, combinations of these two common i.v. anaesthetics agents could be developed to protect the brain from ischaemia. An N-methyl-d-aspartate (NMDA) blocker, ketamine, has been shown to be neuroprotective both in vivo and in vitro. However, ketamine is not commonly recommended for use in patients suffering from cerebral ischaemia because of its adverse neurological effects. We hypothesized that combined administration of ketamine and thiopental sodium (TPS) would be highly effective in protecting cerebral cortical neurones from ischaemia, with possibly reduced dosages. We examined the degree of neuroprotection provided by various concentrations of ketamine and TPS, alone and in combination, in cortical cultures exposed to NMDA or a nitric oxide-releasing compound (NOC-5) for 24 h. The survival rate (SR) of E16 Wistar rat cortical neurones was evaluated using photomicrographs before and after exposure to these compounds. The SRs of cortical neurones exposed to 30 μM NMDA or NOC-5 were 15.0 (3.8)%, 12.8 (3.1)%, respectively. Higher doses (5, 10 and 50 μM) but not lower doses (<1 μM) of ketamine improved SRs [57.9 (2.2)%, 61.1 (5.4)%, 76.7 (3.0)%, respectively] against NMDA but not NOC. Enhanced survival was observed with combined administration of 5 or 10 μM ketamine and 50 μM TPS [SR 71.3 (4.8)%, 74.7 (3.7)%, respectively, P<0.05 if ketamine alone, P<0.01 if TPS alone], against NMDA-induced neurotoxicity in vitro. Only the highest dose of TPS (50 μM) improved survival after NOC exposure. This neuroprotection was not influenced by ketamine. These data indicate that a low, clinically relevant dose of ketamine offer significant neuroprotection during prolonged exposure to NMDA but not to NOC. Combinations of reduced doses of ketamine and TPS exhibited enhanced neuroprotection against NMDA-induced neurotoxicity. Hence, combinations of these two common i.v. anaesthetics agents could be developed to protect the brain from ischaemia.