Chlortetracycline and demeclocycline inhibit calpains and protect mouse neurons against glutamate toxicity and cerebral ischemia.
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.
Jiang
Susan X
SX
Neurophysiology Group, National Research Council Institute for Biological Sciences, National Research Council Canada, Ottawa, Ontario K1A 0R6, Canada.
Lertvorachon
Jittiwud
J
Hou
Sheng T
ST
Konishi
Yasuo
Y
Webster
Jacqueline
J
Mealing
Geoff
G
Brunette
Eric
E
Tauskela
Joseph
J
Preston
Edward
E
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018929:Cell Culture Techniques; D002751:Chlortetracycline / Q000494:pharmacology*; D003707:Demeclocycline / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D003707:Demeclocycline; D002154:Calpain; D002118:Calcium; D002751:Chlortetracycline