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Antimicrobial Agents and Chemotherapy, February 2008, p. 684-693, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00874-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

D. Caridha,¹ D. Yourick,² M. Cabezas,² L. Wolf,² T. H. Hudson,¹ and G. S. Dow^1*

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, Maryland 20910,¹ Division of Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, Maryland 20910²

Received 4 July 2007/ Returned for modification 27 August 2007/ Accepted 1 November 2007

In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-D-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Second, we compared the disruptive effects of mefloquine on calcium homeostasis to those of ionomycin in neuronal and nonneuronal cells. Ionomycin is known to discharge the ER calcium store (through an undefined mechanism), which induces capacitative calcium entry (CCE). In radioligand binding assays, mefloquine showed no affinity for the known binding sites of several glutamate receptor subtypes. The pattern of neuroprotection induced by a panel of glutamate receptor antagonists was dissimilar to that of mefloquine. Both mefloquine and ionomycin exhibited dose-related and qualitatively similar disruptions of calcium homeostasis in both neurons and macrophages. The influx of external calcium was blocked by the inhibitors of CCE in a dose-related fashion. Both mefloquine and ionomycin upregulated the IP3 pathway in a manner that we interpret to be secondary to CCE. Collectively, these data suggest that mefloquine does not activate glutamate receptors and that it disrupts calcium homeostasis in mammalian cells in a manner similar to that of ionomycin.

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* Corresponding author. Mailing address: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910. Phone: (301) 319-9009. Fax: (301) 319-9449. E-mail: geoffrey.dow{at}na.amedd.army.mil

Published ahead of print on 12 November 2007.

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Antimicrobial Agents and Chemotherapy, February 2008, p. 684-693, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.00874-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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