Only extra-high dose of ketamine affects l-glutamate-induced intracellular Ca(2+) elevation and neurotoxicity.
The neurotoxic effects of anesthetics on the developing brain are a concern. Although most of the anesthetics are GABAA agonists or NMDA antagonists, the differences in these effects on prospective glutamate-neurotoxicity in the brain is not fully understood. We examined the degree of L-glutamate-induced intracellular calcium ([Ca(2+)]i) elevation and neurotoxicity in neurons exposed to anesthetics. Primary cortical neurons from E17 rats were preincubated with 1-100 μM of ketamine or thiopental sodium (TPS) for the first 72 h of culturing. Two weeks later, the neurons were exposed to L-glutamate. The extent of glutamate toxicity was evaluated using Ca(2+)-imaging and morphological experiments. Preincubation with 100 μM ketamine but not with other concentrations of ketamine and TPS for the first 72 h in culture significantly enhanced L-glutamate-induced [Ca(2+)]i elevation 2 weeks later. Morphology experiments showed that vulnerability to L-glutamate-mediated neurotoxicity was only altered in neurons preincubated with 100 μM ketamine but not with TPS. Although preincubation with high concentration of ketamine showed enhancement of L-glutamate-induced [Ca(2+)]i elevation 2 weeks later, long-term exposure to TPS or ketamine at clinical doses during developmental periods may not result in a dose-related potentiation of exogenous glutamate-induced neurotoxicity, once the intravenous anesthetics are discontinued.
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine D7, Osaka University, 2-2, Yamadaoka, Suita 565-0871, Japan. Electronic address: shibuta@anes.med.osaka-u.ac.jp.
Satoshi
S
Shibuta
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine D7, Osaka University, 2-2, Yamadaoka, Suita 565-0871, Japan. Electronic address: acpe0193@mac.com.
Tomotaka
T
Morita
Center for Medical Science, International University of Health and Welfare, 2600-1 Kita-Kanemaru, Ohtawara, Tochigi 324-8501, Japan. Electronic address: junksk@iuhw.ac.jp.
Jun
J
Kosaka
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine D7, Osaka University, 2-2, Yamadaoka, Suita 565-0871, Japan. Electronic address: kamib@anes.med.osaka-u.ac.jp.
Takahiko
T
Kamibayashi
Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine D7, Osaka University, 2-2, Yamadaoka, Suita 565-0871, Japan. Electronic address: fujino@anes.med.osaka-u.ac.jp.
Yuji
Y
Fujino
D018686:Anesthetics, Intravenous / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018755:GABA Agonists / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity*; D007649:Ketamine / Q000633:toxicity*; D017208:Rats, Wistar; D013874:Thiopental / Q000633:toxicity*
D018686:Anesthetics, Intravenous; D018755:GABA Agonists; D018698:Glutamic Acid; D007649:Ketamine; D013874:Thiopental; D002118:Calcium
Developing brain; Intracellular calcium; Ketamine; Neuron; Thiopental sodium; l-glutamate