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. 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. Stroke is one of the most common life-threatening neurological diseases. Despite significant advances in the understanding of the molecular events following cerebral ischemia, there are still no potent neuroprotective therapeutics against stroke-induced brain damage (1Hou S.T. MacManus J.P. 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Glutamate overactivates NMDA 2The abbreviations used are: NMDA, N-methyl-d-aspartate; SBP, spectrin breakdown product; CTC, chlortetracycline; DMC, demeclocycline; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CGN, cerebellar granule neuron; CFDA, 5-(6)-carboxyfluorescein diacetate; MCAO, middle cerebral artery occlusion; TTC, 2,3,5-triphenyltetrazolium chloride; AFC, 7-amino-4-trifluoromethylcoumarin; ALLN, acetyl-Leu-Leu-norleucinal. receptors, causing increased intracellular Ca2+ influx leading to the accumulation of toxic levels of intracellular calcium ions (4Lee J.M. Zipfel G.J. Choi D.W. Nature. 1999; 399: A7-A14Crossref PubMed Scopus (1004) Google Scholar, 5Zipfel G.J. Babcock D.J. Lee J.M. Choi D.W. J. Neurotrauma. 2000; 17: 857-869Crossref PubMed Scopus (245) Google Scholar). Elevation in intracellular Ca2+ concentrations activates Ca2+-dependent proteases, such as calpains, which break down critical structural proteins causing neuronal death (3Xiong Z.G. Zhu X.M. 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Neurol. 2004; PubMed Scopus Google Scholar). In the the protective effects of two tetracyclines against glutamate-mediated and cerebral brain The potential molecular mechanisms of such neuroprotection were also CTC and DMC were to be not through inhibition of the NMDA receptor through suppression of a Ca2+ rise and inhibition of calpain activities. and were from from from from size were from to spectrin breakdown products were from J. Durkin as (11Hewitt K.E. Lesiuk H.J. Tauskela J.S. Morley P. Durkin J.P. J. Neurosci. Res. 1998; 54: 223-232Crossref PubMed Scopus (31) Google Scholar), and from and were from of from Minocycline CTC and DMC were from of were from to as S.T. A. G. T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, T. S.T. Brain Res. Mol. Brain Res. 2003; PubMed Scopus Google Scholar). were and of and in a to the and to break from of and were to the neurons to in and to to in and with to a of were at a of to a of to cell were with in of culture Tetracyclines were to in vitro cultured at to treatment with glutamate The were at were also the of the treatment neuronal the as S.T. A. G. T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, T. S.T. Brain Res. Mol. Brain Res. 2003; PubMed Scopus Google Scholar). The to a of were with of the at 30 The of a at and against the from the were also in and in to a of treatment in at experiments has been D.L. R.J. Morley P. J. Pharmacol. Exp. 2001; Google Scholar). cultured culture were at at a The also 30 and were from used to NMDA of NMDA and the The at currents were an with a with a and were a and were at a potential of The of currents to the I I is the NMDA, and is the NMDA in the of the at the of the calcium as J.S. E. R. T. Morley P. J. 2003; Scopus Google Scholar). culture in the with a calcium in a the and were with the with the at were a at and NMDA to the and in were and The in Ca2+ the from the of the of CTC DMC glutamate-induced in intracellular Ca2+ of at in vitro were with 30 at with and and in the were a with and at with a in the of to the as G. M. J. Biol. Chem. Full Text PDF PubMed Scopus Google Scholar) and K.W. J. 2004; PubMed Scopus Google Scholar). The in one of The and and were from a of and The to be as K.W. J. 2004; PubMed Scopus Google Scholar). The of the of the in which also and glutamate and the were at The were were the of following the the were from and were to an as J.P. M. E. I. J. J. 2003; PubMed Scopus Google Scholar, A. T.C. M. A. C. L. J. H. P. R.P. A. R.T. S.T. Lynch G. J. PubMed Scopus Google Scholar). of MCAO, the to normal and were with CTC DMC at ischemia, The no treatment in which were with the of were and the brain infarction as as size a 2,3,5-triphenyltetrazolium as J.P. M. E. I. J. J. 2003; PubMed Scopus Google Scholar, A. T.C. M. A. C. L. J. H. P. R.P. A. R.T. S.T. Lynch G. J. PubMed Scopus Google Scholar). were and which were with of at the with and to a of which to the in the the were with in and in at in a and the were in brain in the ischemic side of the brain compared with the side of the brain of the animal the following of ischemic of J.P. M. E. I. J. J. 2003; PubMed Scopus Google Scholar, A. T.C. M. A. C. L. J. H. P. R.P. A. R.T. S.T. Lynch G. J. PubMed Scopus Google Scholar, E. J. J. Neurosci. 2000; PubMed Scopus Google Scholar) and used the were at and an to the treatment of the The neurological were as with to to the to to and immediate than the of the severe of were and were Calpain a calpain following the The is of of calpain a The in the release of that be in a calpain I II from activated Ca2+ and with CTC DMC minocycline calpain and of calpain to a of The at in the The of the in the release of that be the at and at in a and a in and as S.T. A. G. T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The with a to calpain of brain spectrin at with to the at of the a and were and and the significant CTC and DMC against Glutamate neuroprotective effects of CTC, DMC, and minocycline against glutamate-mediated in cultured were examined and the compounds showed potent neuroprotection against glutamate-mediated toxicity to in a and than of the were these two compounds at and to following glutamate treatment than of the The of neurons of the CTC and DMC were not toxic to at the of not CTC and DMC Brain minocycline has been shown to provide neuroprotection against cerebral ischemia, examined the neuroprotective of CTC and DMC in a of focal ischemia with to at and two and 16 following at were to the brain as compounds significantly the size in the cerebral in with the ischemic and brain and of the brain as were shown in of the in the two brain in the cerebral and as the in The infarction significantly in the in with CTC DMC The protective effects of these compounds were also the of the neurological of the ischemic the as in the the of the neurological of ischemic were compared with of ischemic and shown in with the two compounds showed significant of compared with the ischemic that CTC and DMC neurological CTC and DMC NMDA and the in the mechanisms of neuroprotection CTC and DMC, examined whether these two compounds blocked calcium through the NMDA receptor, which has been in glutamate-induced compounds at showed to NMDA-induced currents of NMDA CTC in a in NMDA-induced of NMDA DMC a 16 in NMDA-induced NMDA activation intracellular Ca2+ influx, whether these two compounds glutamate and NMDA-induced intracellular Ca2+ shown in NMDA intracellular calcium influx increased the of The of the two compounds blocked influx, the increased to the as that of Minocycline also a similar of of Ca2+ influx as compared with from CTC and DMC at the and compared with Ca2+ the MK-801, an to NMDA receptor, blocked glutamate and NMDA-induced Ca2+ influx and Taken together, these demonstrated that CTC and DMC are and of the NMDA receptor currents and only partially influx the of However, such a in NMDA receptor and influx may not be to the than neuroprotection these two that these compounds may inhibit intracellular CTC and DMC through of Calpain intracellular such as calpain are an of neuronal death in to glutamate toxicity and cerebral ischemia (1Hou S.T. MacManus J.P. Int. Rev. Cytol. 2002; 221: 93-148Crossref PubMed Scopus (168) Google Scholar). caspase may also a in the apoptotic of ischemia-induced neuronal showed that caspase is not in glutamate-induced neuronal death (1Hou S.T. MacManus J.P. Int. Rev. Cytol. 2002; 221: 93-148Crossref PubMed Scopus (168) Google Scholar). CTC and DMC neurons in vitro and in that these two compounds the activities of calpains. in vitro experiments were calpains. CTC and DMC significantly inhibited the activities of calpain I and calpain II to calpains and which inhibited calpain and also neuronal were used as the minocycline, a potent did not inhibit the activities of calpains and examined whether these two compounds inhibit glutamate-induced activation of calpains in Calpain the and the of the shown in and treatment with the of increased significantly and the of a Calpain ALLN, CTC, and DMC, were to cultured 30 to glutamate the calpain and the two compounds significantly the of glutamate treatment in with glutamate only at the two compounds CTC and DMC also inhibited calpain activities in brain as shown the of and The increased in the ischemic brain of the of significantly in and and Taken together, CTC and DMC inhibit calpains activation in to and cerebral ischemia. In the the that CTC and DMC are neuroprotective against glutamate toxicity in cultured in vitro and focal cerebral ischemia in vivo through inhibition of calpains, a mechanism from that of minocycline. the of the is the that CTC and DMC neuroprotection through inhibition of calpain activities. The molecular of CTC and DMC to be of the NMDA CTC and DMC only weakly inhibited NMDA-induced intracellular calcium The inhibition of NMDA the two compounds to the in intracellular Ca2+ levels in the two it is that Ca2+ the potent neuroprotection CTC and DMC to and that these two compounds intracellular death the molecular of CTC and DMC appeared to be from of minocycline in that CTC and DMC inhibit calpain I and II, minocycline Previous studies have demonstrated that minocycline in vivo neuroprotection microglial activation (21Koistinaho J. Yrjanheikki J. Kauppinen T. Koistinaho M. Ernst. Schering Res. Found. Workshop. 2004; 47: 101-115Google Scholar, 22Yrjanheikki J. Tikka T. Keinanen R. Goldsteins G. Chan P.H. Koistinaho J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 13496-13500Crossref PubMed Scopus (941) Google Scholar). also showed that minocycline directly intracellular death to neurons through blocking cytochrome c release and the activation of caspase M. Matute C. Trends Pharmacol. Sci. 2004; 25: 609-612Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 29Zhu S. Stavrovskaya I.G. Drozda M. Kim B.Y. Ona V. Li M. Sarang S. Liu A.S. Hartley D.M. Wu d.C. Gullans S. Ferrante R.J. Przedborski S. Kristal B.S. Friedlander R.M. Nature. 2002; 417: 74-78Crossref PubMed Scopus (980) Google Scholar). The in vitro studies cultured showed that neuroprotection CTC and DMC from inhibition of calpain activities not from inhibition of microglial microglial activation no in such glutamate-induced neuronal death In addition, caspase did not activated in (1Hou S.T. MacManus J.P. Int. Rev. Cytol. 2002; 221: 93-148Crossref PubMed Scopus (168) Google Scholar). in vitro and in vivo as shown in demonstrated that CTC and DMC were potent of calpains activated in to both glutamate treatment and in are major that are activated following ischemic injury to the brain and are the rapid and sustained of spectrin breakdown in the J.M. Savage M.J. Marcy V.R. Pinsker L.R. Siman R. J. Neurosci. 1994; 14: 3934-3944Crossref PubMed Google Scholar, 20Rami A. Neurobiol. Dis. 2003; 13: 75-88Crossref PubMed Scopus (149) Google Scholar, T. 2004; PubMed Scopus Google Scholar). The in vitro calpain and demonstrated that calpain increased following treatment with glutamate in cultured and that be CTC and in calpain following cerebral ischemia is with that be as as in the of in the and in and of the ischemic rats J.M. Savage M.J. Marcy V.R. Pinsker L.R. Siman R. J. Neurosci. 1994; 14: 3934-3944Crossref PubMed Google Scholar). In to the activities of calpain are also in a of such as brain and Y. Trends Mol. Med. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). a calpain have been developed to these diseases, example, and Curr. Med. Chem. 2000; PubMed Scopus Google Scholar). However, of have structural to tetracycline may inhibit calpain in a from in the and which with the potential to a as therapeutics to stroke has to such as that the not with normal physiological functions of glutamate receptors, that the intracellular death to provide to and that the the brain and have CTC and DMC used in the to of the CTC and DMC have been used as In addition, tetracyclines also have activities and properties such as and S.C. D.J. Xu L. A. G. D.C. Exp. Neurol. 2004; PubMed Scopus Google Scholar, H. M. J. Y. Y. Google Scholar, M.E. Res. 1998; PubMed Scopus Google Scholar). of tetracyclines leads as stroke However, of CTC and DMC is these compounds are potent it is to at and a of The that used in the were to and with no toxicity a very that minocycline to cerebral ischemia and neuroprotection in rats L. S.C. D. J. Hill G. D.C. Neurol. 2004; 4: PubMed Scopus Google Scholar). is to the of CTC and In addition, of CTC and DMC, which not anti-microbial are In a of experiments in the demonstrated that CTC and DMC, the two used provide neuroprotection not through blocking NMDA inhibition of calpain activity. of these two compounds may to of neuroprotection following cerebral ischemia. We and

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