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J. Biol. Chem., Vol. 280, Issue 40, 33811-33818, October 7, 2005

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Chlortetracycline and Demeclocycline Inhibit Calpains and Protect Mouse Neurons against Glutamate Toxicity and Cerebral Ischemia^*

Susan X. Jiang, Jittiwud Lertvorachon, Sheng T. Hou1, Yasuo Konishi, Jacqueline Webster, Geoff Mealing, Eric Brunette, Joseph Tauskela, and Edward Preston

From the Neurophysiology Group, National Research Council Institute for Biological Sciences, National Research Council Canada, Ottawa, Ontario K1A 0R6, Canada and the Chemical Biology Group, National Research Council Biotechnology Research Institute, National Research Council Canada, Montreal, Quebec H4P 2R2, Canada

Minocycline is a potent neuroprotective tetracycline in animal models of cerebral ischemia. We examined the protective properties of chlortetracycline (CTC) and demeclocycline (DMC) and showed that these two tetracyclines were also potent neuroprotective against glutamate-induced neuronal death in vitro and cerebral ischemia in vivo. However, CTC and DMC appeared to confer neuroprotection through a unique mechanism compared with minocycline. Rather than inhibiting microglial activation and caspase, CTC and DMC suppressed calpain activities. In addition, CTC and DMC only weakly antagonized N-methyl-D-aspartate (NMDA) receptor activities causing 16 and 14%, respectively, inhibition of NMDA-induced whole cell currents and partially blocked NMDA-induced Ca²⁺ influx, commonly regarded as the major trigger of neuronal death. In vitro and in vivo experiments demonstrated that the two compounds selectively inhibited the activities of calpain I and II activated following glutamate treatment and cerebral ischemia. In contrast, minocycline did not significantly inhibit calpain activity. Taken together, these results suggested that CTC and DMC provide neuroprotection through suppression of a rise in intracellular Ca²⁺ and inhibition of calpains.

Received for publication, March 21, 2005 , and in revised form, July 26, 2005.

^* This work was supported in part by research grants from the Genomics and Health Initiatives of National Research Council and Heart and Stroke Foundation of Ontario Grant-in-aid NA5393 (to S. T. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Neurophysiology Group, NRC Inst. for Biological Sciences, National Research Council Canada, 1200 Montreal Rd., Bldg. M54, Ottawa, ON, K1A 0R6, Canada. Tel.: 613-993-7764; Fax: 613-941-7764; E-mail: sheng.hou{at}nrc-cnrc.gc.ca.

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