In monolayers of cultured rat astrocytes a number of agents that induce oxidative stress act synergistically with exposure to copper leading to rapid depolarization of the mitochondrial membrane potential (Y m ) and increased reactive oxygen species (ROS) production. Copper sensitized astrocytes to the action of menadione, an intracellular generator of superoxide anion radical, exogenous hydrogen peroxide (H 2 O 2 ) and rotenone, an inhibitor of mitochondrial electron transport chain complex I. However, significant differences were observed in the ability to modulate the copper-enhanced oxidative stress depending on which stressor was used. The inhibitor of mitochondrial permeability transition cyclosporin A attenuated the effect of copper and rotenone, but had no protective action in the case of H 2 O 2 /copper and menadione/copper combinations. The H 2 O 2 scavenger pyruvate was effective at protecting mitochondria against damage associated with the combined exposure to H 2 O 2 /copper and menadione/copper but not to the rotenone/copper combination. The antioxidant Trolox was ineffective at protecting against any of these actions and indeed had a damaging effect when combined with copper. The membrane-permeable copper chelator neocuproine combined with sensitizing concentrations of menadione caused a decrease in Y m , mimicking the action of copper. Penicillamine, a membrane-impermeable copper chelator, was effective at reducing copper sensitization. Endogenous copper, mobilized during periods of oxidative stress, may play a role in the pathophysiology of brain injury. Our results suggest that this might be particularly dangerous in dysfunctional conditions in which the mitochondrial electron transport chain is compromised. Keywords: antioxidants, astrocytes, copper, copper chelators, mitochondrial membrane potential, reactive oxygen species. J. Neurochem. Astrocytes are one of the major cell types in the brain; they protect neurons from various external insults, including reactive oxygen species (ROS) (Desagher et al. 1996;Tanaka et al. 1999). Alterations in astroglial cell function during oxidative stress may thus play a key role in the pathophysiology of brain injury. Mitochondria are highly sensitive to oxidative stress, and ROS production by mitochondria can in turn disturb mitochondrial function causing a vicious cycle. Damage to mitochondria in brain cells may compromise their ability to protect against ROS and indeed lead them to become sources of ROS production (Lenaz 1998;Montal 1998;Sullivan et al. 1999;Beal 2000;Chan 2001).Copper is a transition metal that plays an important functional role in many biological processes (Camakaris et al. 1999;Rinaldi 2000). However, even in a bound form copper is dangerous owing to its ability to increase oxidative stress through conversion of H 2 O 2 to more reactive ROS such as the hydroxyl radical (OHAE) (the Fenton-Haber-Weiss reaction) (Halliwell and Gutteridge 1999). There is evidence that copper can be mobilized and redistributed from cell storage poo...
Motor nerve terminals on abdominal body-wall muscles 6A and 7A in larval flesh flies were investigated to establish their general structural features with confocal microscopy, transmission electron microscopy, and freeze-fracture procedures. As in Drosophila and other dipterans, two motor axons supply these muscles, and two morphologically different terminals were discerned with confocal microscopy: thin terminals with relatively small varicosities (Type Is), and thicker terminals with larger varicosities (Type Ib). In serial electron micrographs, Type Ib terminals were distinguished from Type Is terminals by their larger cross-sectional area, more extensive subsynaptic reticulum, more mitochondrial profiles, and more clear synaptic vesicles. Type Ib terminals possessed larger synapses and more synaptic contact area per unit terminal length. Although presynaptic dense bars of active zones were similar in mean length for the two terminal types, there were almost twice as many dense bars per synapse for Type Ib terminals. Freeze-fractures through the presynaptic membrane showed particle-free areas indicative of synapses on the P-face, within which were localized aggregations of large intramembranous particles indicative of active zones. These particles were similar in number to those found at active zones of several other arthropod neuromuscular junctions. In general, synaptic structural parameters strongly paralleled those of the anatomically homologous muscles in Drosophila melanogaster. In live preparations, simultaneous focal recording from identified varicosities and intracellular recording indicated that the two terminals produced excitatory junction potentials of similar amplitude in a physiological solution similar to that used for Drosophila.
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