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Midazolam and ketamine inhibit glutamate release via a cloned human brain glutamate transporter

From the Department of Anesthesiology and Critical Care Medicine, Tokyo Medical and Dental, University, 5-45, Yushima 1-chome, Bunkyo-ku, Tokyo, 113-8519 Japan.

Address correspondence to: Address correspondence to: Dr. F. Sakai. Phone: 81-3-5803-5325; Fax: 81-3-5803-0149; E-mail: sakai.mane{at}med.tmd.ac.jp

Purpose: In cerebral ischemia/anoxia, the glutamate transporter runs in reverse and releases glutamate into the extracellular space, causing irreversible neuronal damage. Intravenous anesthetics attenuate overall glutamate release and prevent neuronal injury during anoxia/ischemia, but their effect on the glutamate transporter is variable.

Methods: A human glial glutamate transporter (hGLT-1) cDNA was isolated by screening a human cerebral cortical library. Cloned cDNA was transfected in Chinese hamster ovary cells. The effect of the intravenous anesthetics midazolam (0.3 to 30 µM), ketamine (10 to 100 µM), thiopental (30 to 300 µM), and propofol (3 to 30 µM) on reversed uptake of Lglutamate via hGLT-1 was examined by whole-cell patch-clamp.

Results: Midazolam at a concentration 3 µM reduced outward currents arising from reversed L-glutamate uptake via hGLT-1 in a concentration-dependent manner. While, ketamine at 100 µM attenuated the same outward currents, to 53.3 ± 11.4% of those seen in controls without anesthetics (P < 0.05, n=5). In contrast, neither thiopental nor propofol showed effects on outward currents mediated by reversed operation of hGLT-1.

Conclusions: These results suggest that midazolam and ketamine, but not thiopental and propofol, have a capacity to inhibit glutamate release via GLT-1 directly.

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