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Anesth Analg 2002;95:373-378
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Midazolam Induces Expression of c-Fos and EGR-1 by a Non-GABAergic Mechanism

Kazuhiko Fukuda, MD, Takehiro Shoda, MD, Hiroyuki Mima, MD, and Hisatoshi Uga, MD

Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan

Address correspondence and reprint requests to Kazuhiko Fukuda, MD, Department of Anesthesia, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Address e-mail to kfukuda{at}kuhp.kyoto-u.ac.jp

Gene expression changes induced by general anesthetics have not been extensively examined. In this investigation, we treated rat pheochromocytoma PC12 cells with IV anesthetics, and assessed expression of immediate early gene products, c-Fos and EGR-1, by immunoblot analysis. Thiopental, ketamine, propofol, and diazepam did not significantly change the expression level of c-Fos and EGR-1. In contrast, midazolam dose- and time-dependently induced expression of c-Fos and EGR-1, which was not affected by antagonists of the benzodiazepine receptors, flumazenil and PK11195. The midazolam-induced c-Fos and EGR-1 expression was abolished by PD98059, an inhibitor for mitogen- activated protein kinase/extracellular signal-regulated kinase kinase, suggesting the involvement of extracellular signal-regulated kinases (ERKs). Immunoblot analysis demonstrated that midazolam induces phosphorylation and activation of ERKs. These results indicate that midazolam induces the expression of c-Fos and EGR-1, by activation of ERKs through a mechanism independent from {gamma}-aminobutyric acidA receptors, in PC12 cells, and suggest the possibility that midazolam can induce long-term changes of neural functions by changing gene expression.

IMPLICATIONS: Gene expression changes induced by anesthetics in neuronal cells have not been noticed. We demonstrate that a large concentration of midazolam can induce expression of immediate early genes by a non-GABAergic mechanism in PC12 cells, suggesting that the administration of midazolam might lead to long-term changes of neural functions by changing gene expression.






Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2002 by the International Anesthesia Research Society.