INVESTIGADORES
SANZ BLASCO Sara Isabel
artículos
Título:
Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells
Autor/es:
GARCÍA-MARTÍNEZ EM; SANZ BLASCO S; KARACHITOS A; BANDEZ MJ; FERNANDEZ-GOMEZ FJ; PEREZ-ALVAREZ S; DE MERA RM; JORDAN MJ; AGUIRRE N; GALINDO MF; VILLALOBOS C; NAVARRO A; KMITA H; JORDÁN J
Revista:
BIOCHEMICAL PHARMACOLOGY
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2009 vol. 79 p. 239 - 250
ISSN:
0006-2952
Resumen:
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 Ca2+ concentrations in a reversible manner. Moreover, minocycline added in the course of NMDA stimulation decreased Ca2+ 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 Ca2+ 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 μM Ca2+ 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.