ubiquinone and Endotoxemia

Topics: Animals; Endotoxemia; Hydrogen Peroxide; Mitochondria; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxynitrous Acid; Tissue Distribution; Ubiquinone

Sepsis, a leading cause of mortality in intensive care units worldwide, is often a result of overactive and systemic inflammation following serious infections. We found that mice lacking immediate early responsive gene X-1 (IEX-1) were prone to lipopolysaccharide (LPS) -induced endotoxemia. A nonlethal dose of LPS provoked numerous aberrations in IEX-1 knockout (KO) mice including pancytopenia, increased serum aspartate aminotransferase (AST), and lung neutrophilia, concurrent with liver and kidney damage, followed by death. Given these results, in conjunction with a proven role for IEX-1 in the regulation of reactive oxygen species (ROS) homeostasis during stress, we pre-treated IEX-1 KO mice with Mitoquinone (MitoQ), a mitochondrion-based antioxidant prior to LPS injection. The treatment significantly reduced ROS formation in circulatory cells and protected against pancytopenia and multiple organ failure, drastically increasing the survival rate of IEX-1 KO mice challenged by this low dose of LPS. This study confirms significant contribution of mitochondrial ROS to the etiology of sepsis.

Topics: Animals; Antioxidants; Blood Cell Count; Data Interpretation, Statistical; Endotoxemia; Endotoxins; Immediate-Early Proteins; Kaplan-Meier Estimate; Kidney; Liver; Lung; Membrane Potential, Mitochondrial; Mice, Knockout; Mitochondria; Organophosphorus Compounds; Reactive Oxygen Species; Ubiquinone

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6'-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg x kg(-1) x day(-1)), saline + MitoQ (500 microM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Caspase 3; Caspase 9; Cell Respiration; Disease Models, Animal; Drug Administration Schedule; Endotoxemia; Enzyme Activation; Heart Diseases; Mice; Mitochondria, Heart; Myocardial Contraction; Myocardium; Organophosphorus Compounds; Protein Carbonylation; Rats; Tumor Necrosis Factor-alpha; Ubiquinone; Ventricular Function, Left; Ventricular Pressure

Burn trauma increased blood chemiluminescence, while lipopolysaccharide in a dose of 1 mg/kg potentiated this effect, activated LPO, and decreased plasma antioxidant activity. In erythrocytes, superoxide dismutase activity increased, while activity of peroxide-utilizing enzymes decreased. Myeloperoxidase content increased in the lungs and epidermis. The preparation of alpha-tocopherol, selenium aspartate, and ubiquinone abolished the effect of lipopolysaccharide, but did not modulate the increase in chemiluminescence under the influence of this agent.

Topics: alpha-Tocopherol; Animals; Antioxidants; Burns; Endotoxemia; Epidermis; Erythrocytes; Lipid Peroxidation; Lipopolysaccharides; Luminescent Measurements; Lung; Male; Neutrophils; Peroxidase; Rats; Rats, Wistar; Selenium Compounds; Superoxide Dismutase; Ubiquinone

Topics: Animals; Antioxidants; Cardiovascular Diseases; Coenzymes; Endotoxemia; Neuroprotective Agents; Rats; Ubiquinone

Coenzyme Q10 (CoQ10, ubiquinone) is a highly mobile electron carrier in the mitochondrial respiratory chain that also acts as an antioxidant. We evaluated the neuroprotective efficacy of CoQ10 against fatality in an experimental model of endotoxemia that mimics systemic inflammatory response syndrome using a novel water-soluble formulation of this quinone derivative. Experiments were conducted in adult male Sprague-Dawley rats that were maintained under propofol anesthesia. Intravenous administration of Escherichia coli lipopolysaccharide (LPS; 30 mg/kg) induced progressive hypotension, with death ensuing within 4 h. The sequence of cardiovascular events during this LPS-induced endotoxemia can be divided into a reduction (Phase I), followed by an augmentation (Phase II; "pro-life" phase) and a secondary decrease (Phase III; "pro-death" phase) in the power density of the vasomotor components (0-0.8 Hz) of systemic arterial pressure signals. Pretreatment by microinjection bilaterally of CoQ10 (1 or 2 microg) into the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor tone, significantly diminished mortality, prolonged survival time, and reduced the slope or magnitude of the LPS-induced hypotension. CoQ10 pretreatment also significantly prolonged the duration of and augmented the total power density of the vasomotor components of systemic arterial pressure signals in Phase II endotoxemia. The increase in superoxide anion production induced by LPS at the RVLM during Phases II and III endotoxemia was also significantly blunted. We conclude that CoQ10 provides neuroprotection against fatality during experimental endotoxemia by reducing superoxide anion production at the RVLM, whose neuronal activity is intimately related to the "life-and-death" process.

Topics: Animals; Coenzymes; Disease Models, Animal; Endotoxemia; Escherichia coli; Lipopolysaccharides; Male; Medulla Oblongata; Microinjections; Rats; Rats, Sprague-Dawley; Superoxides; Survival Rate; Time Factors; Ubiquinone