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


METHODS
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.


RESULTS
The SRs of cortical neurones exposed to 30 microM NMDA or NOC-5 were 15.0 (3.8)%, 12.8 (3.1)%, respectively. Higher doses (5, 10 and 50 microM) but not lower doses (<1 microM) 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 microM ketamine and 50 microM 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 microM) improved survival after NOC exposure. This neuroprotection was not influenced by ketamine.


CONCLUSIONS
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.
Shibuta
S
S
Department of Anaesthesiology and Intensive Care Medicine, Graduate School of Medicine D7, Osaka University 2-2, Yamadaoka, Suita 565-0871, Japan. shibuta@anes.med.osaka-u.ac.jp
Varathan
S
S
Mashimo
T
T
D000778:Anesthetics, Dissociative / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D007649:Ketamine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013874:Thiopental / Q000494:pharmacology*; D014226:Triazenes / Q000494:pharmacology
C114535:1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene; D000778:Anesthetics, Dissociative; D018686:Anesthetics, Intravenous; D004338:Drug Combinations; D018696:Neuroprotective Agents; D014226:Triazenes; D016202:N-Methylaspartate; D007649:Ketamine; D013874:Thiopental