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

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DOIResolve DOI: http://doi.org/10.1074/jbc.M503113200
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TypeArticle
Journal titleJournal Of Biological Chemistry
J. Biol. Chem.
Volume280
Issue40
Pages3381133818; # of pages: 8
SubjectNeurons; toxicity
AbstractMinocycline 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.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada; NRC Institute for Biological Sciences; NRC Biotechnology Research Institute
Peer reviewedNo
NRC numberJIANG2005
NPARC number12328993
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Record identifier2157ee08-b549-4faf-b111-443417202dec
Record created2009-09-10
Record modified2016-05-09
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