oligomycins and idebenone

In this study, we investigated the involvement of reactive oxygen species (ROS) and calcium in staurosporine (STS)-induced apoptosis in cultured retinal neurons, under conditions of maintained membrane integrity. The antioxidants idebenone (IDB), glutathione-ethylester (GSH/EE), trolox, and Mn(III)tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly reduced STS-induced caspase-3-like activity and intracellular ROS generation. Endogenous sources of ROS production were investigated by testing the effect of the following inhibitors: 7-nitroindazole (7-NI), a specific inhibitor of the neuronal isoform of nitric oxide synthase (nNOS); arachidonyl trifluoromethyl ketone (AACOCF(3)), a phospholipase A(2) (PLA(2)) inhibitor; allopurinol, a xanthine oxidase inhibitor; and the mitochondrial inhibitors rotenone and oligomycin. All these compounds decreased caspase-3-like activity and ROS generation, showing that both mitochondrial and cytosolic sources of ROS are implicated in this mechanism. STS induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)), which was partially prevented in the presence of IDB and GSH/EE, indicating its dependence on ROS generation. These two antioxidants and the inhibitors allopurinol and 7-NI also reduced the number of TdT-mediated dUTP nick-end labeling-positive cells. Thus, endogenous ROS generation and the rise in intracellular calcium are important inter-players in STS-triggered apoptosis. Furthermore, the antioxidants may help to prolong retinal cell survival upon apoptotic cell death.

Topics: Adenine; Allopurinol; Animals; Antioxidants; Apoptosis; Arachidonic Acids; Benzoquinones; Blotting, Western; Calcium; Carbon; Caspase 3; Caspases; Cell Death; Cell Survival; Chick Embryo; Chromans; Coloring Agents; Cytosol; DNA Fragmentation; Enzyme Inhibitors; Glutathione; In Situ Nick-End Labeling; Indazoles; Metalloporphyrins; Mitochondria; Neurons; Nitric Oxide Synthase; Oligomycins; Protein Isoforms; Reactive Oxygen Species; Retina; Rotenone; Staurosporine; Tetrazolium Salts; Thiazoles; Time Factors; Ubiquinone; Uncoupling Agents; Xanthine Oxidase

Effect of WEB 1881 FU on hypoglycemia/hypoxia-induced brain damage in rats was evaluated and compared to findings obtained with idebenone. We used an in vitro model that facilitated the direct monitoring of dopamine release from striatal slices. The response to high K+ stimulation under perfusion of the slices with D-glucose-free Ringer solution (hypoglycemia) decreased at 40 min, and then practically disappeared. WEB 1881 FU at 10(-6) M or idebenone at 10(-6) M significantly protected against impairment of the striatal responses under the conditions of hypoglycemia. Hypoglycemic injury, evidenced by a remarkable neuron loss, necrosis and spongyosis was also ameliorated by these drugs. WEB 1881 FU at 10(-6) M had a protective action against the impairment of striatal responses evoked by NaCN (electron transport inhibitor at site 3) and oligomycin (inhibitor of mitochondrial ATP synthesis), but idebenone at 10(-6) M did not. In light of these observations, the possibility that WEB 1881 FU and idebenone exert neuroprotective actions against hypoglycemic/hypoxic brain injury by activating energy metabolism with different mechanisms from each other has to be considered.

Topics: Animals; Benzoquinones; Brain Diseases; Corpus Striatum; Cyanides; Dopamine; Hypoglycemia; Hypoxia; In Vitro Techniques; Male; Neurons; Oligomycins; Parasympatholytics; Potassium; Pyrrolidinones; Quinones; Rats; Rats, Inbred Strains; Ubiquinone