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Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells.

Abstract

Minocycline, an antibiotic of the tetracycline family, has attracted considerable interest for its theoretical therapeutic applications in neurodegenerative diseases. However, the mechanism of action underlying its effect remains elusive. Here we have studied the effect of minocycline under excitotoxic conditions. Fluorescence and bioluminescence imaging studies in rat cerebellar granular neuron cultures using fura2/AM and mitochondria-targeted aequorin revealed that minocycline, at concentrations higher than those shown to block inflammation and inflammation-induced neuronal death, inhibited NMDA-induced cytosolic and mitochondrial rises in Ca(2+) concentrations in a reversible manner. Moreover, minocycline added in the course of NMDA stimulation decreased Ca(2+) intracellular levels, but not when induced by depolarization with a high K(+) medium. We also found that minocycline, at the same concentrations, partially depolarized mitochondria by about 5-30 mV, prevented mitochondrial Ca(2+) uptake under conditions of environmental stress, and abrogated NMDA-induced reactive oxygen species (ROS) formation. Consistently, minocycline also abrogates the rise in ROS induced by 75 microM Ca(2+) in isolated brain mitochondria. In search for the mechanism of mitochondrial depolarization, we found that minocycline markedly inhibited state 3 respiration of rat brain mitochondria, although distinctly increased oxygen uptake in state 4. Minocycline inhibited NADH-cytochrome c reductase and cytochrome c oxidase activities, whereas the activity of succinate-cytochrome c reductase was not modified, suggesting selective inhibition of complexes I and IV. Finally, minocycline affected activity of voltage-dependent anion channel (VDAC) as determined in the reconstituted system. Taken together, our results indicate that mitochondria are a critical factor in minocycline-mediated neuroprotection.

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  • Authors+Show Affiliations

    ,

    Neurofarmacología, Dpto Ciencias Médicas, Facultad de Medicina, UCLM, Albacete, Spain.

    , , , , , , , , , , , ,

    Source

    Biochemical pharmacology 79:2 2010 Jan 15 pg 239-50

    MeSH

    Animals
    Calcium
    Calcium Signaling
    Cells, Cultured
    Cerebellum
    Cytoplasmic Granules
    Minocycline
    Mitochondria
    Neuroprotective Agents
    Rats
    Rats, Wistar

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19682437

    Citation

    Garcia-Martinez, Eva Maria, et al. "Mitochondria and Calcium Flux as Targets of Neuroprotection Caused By Minocycline in Cerebellar Granule Cells." Biochemical Pharmacology, vol. 79, no. 2, 2010, pp. 239-50.
    Garcia-Martinez EM, Sanz-Blasco S, Karachitos A, et al. Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochem Pharmacol. 2010;79(2):239-50.
    Garcia-Martinez, E. M., Sanz-Blasco, S., Karachitos, A., Bandez, M. J., Fernandez-Gomez, F. J., Perez-Alvarez, S., ... Jordán, J. (2010). Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochemical Pharmacology, 79(2), pp. 239-50. doi:10.1016/j.bcp.2009.07.028.
    Garcia-Martinez EM, et al. Mitochondria and Calcium Flux as Targets of Neuroprotection Caused By Minocycline in Cerebellar Granule Cells. Biochem Pharmacol. 2010 Jan 15;79(2):239-50. PubMed PMID: 19682437.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. AU - Garcia-Martinez,Eva Maria, AU - Sanz-Blasco,Sara, AU - Karachitos,Andonis, AU - Bandez,Manuel J, AU - Fernandez-Gomez,Francisco J, AU - Perez-Alvarez,Sergio, AU - de Mera,Raquel Maria Melero Fernandez, AU - Jordan,Maria J, AU - Aguirre,Norberto, AU - Galindo,Maria F, AU - Villalobos,Carlos, AU - Navarro,Ana, AU - Kmita,Hanna, AU - Jordán,Joaquín, Y1 - 2009/08/12/ PY - 2009/06/04/received PY - 2009/07/29/revised PY - 2009/07/29/accepted PY - 2009/8/18/entrez PY - 2009/8/18/pubmed PY - 2009/12/16/medline SP - 239 EP - 50 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 79 IS - 2 N2 - Minocycline, an antibiotic of the tetracycline family, has attracted considerable interest for its theoretical therapeutic applications in neurodegenerative diseases. However, the mechanism of action underlying its effect remains elusive. Here we have studied the effect of minocycline under excitotoxic conditions. Fluorescence and bioluminescence imaging studies in rat cerebellar granular neuron cultures using fura2/AM and mitochondria-targeted aequorin revealed that minocycline, at concentrations higher than those shown to block inflammation and inflammation-induced neuronal death, inhibited NMDA-induced cytosolic and mitochondrial rises in Ca(2+) concentrations in a reversible manner. Moreover, minocycline added in the course of NMDA stimulation decreased Ca(2+) intracellular levels, but not when induced by depolarization with a high K(+) medium. We also found that minocycline, at the same concentrations, partially depolarized mitochondria by about 5-30 mV, prevented mitochondrial Ca(2+) uptake under conditions of environmental stress, and abrogated NMDA-induced reactive oxygen species (ROS) formation. Consistently, minocycline also abrogates the rise in ROS induced by 75 microM Ca(2+) in isolated brain mitochondria. In search for the mechanism of mitochondrial depolarization, we found that minocycline markedly inhibited state 3 respiration of rat brain mitochondria, although distinctly increased oxygen uptake in state 4. Minocycline inhibited NADH-cytochrome c reductase and cytochrome c oxidase activities, whereas the activity of succinate-cytochrome c reductase was not modified, suggesting selective inhibition of complexes I and IV. Finally, minocycline affected activity of voltage-dependent anion channel (VDAC) as determined in the reconstituted system. Taken together, our results indicate that mitochondria are a critical factor in minocycline-mediated neuroprotection. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/19682437/Mitochondria_and_calcium_flux_as_targets_of_neuroprotection_caused_by_minocycline_in_cerebellar_granule_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(09)00685-6 DB - PRIME DP - Unbound Medicine ER -