xjb-5-131 and Disease-Models--Animal

Mitochondrial supercomplexes (SCs) are the large supramolecular assembly of individual electron transport chain (ETC) complexes that apparently provide highly efficient ATP synthesis and reduce electron leakage and reactive oxygen species (ROS) production. Oxidative stress during cardiac ischemia-reperfusion (IR) can result in degradation of SCs through oxidation of cardiolipin (CL). Also, IR induces calcium overload and enhances reactive oxygen species (mitROS) in mitochondria that result in the opening of the nonselective permeability transition pores (PTP). The opening of the PTP further compromises cellular energetics and increases mitROS ultimately leading to cell death. Here, we examined the role of PTP-induced mitROS in disintegration of SCs during cardiac IR. The relationship between mitochondrial PTP, ROS, and SCs was investigated using Langendorff-perfused rat hearts subjected to global ischemia (25 min) followed by short-time (5 min) or long-time (60 min) reperfusion in the presence or absence of the PTP inhibitor, sanglifehrin A (SfA), and the mitochondrial targeted ROS and electron scavenger, XJB-5-131. Also, the effects of CL deficiency on SC degradation, PTP, and mitROS were investigated in tafazzin knockdown (TazKD) mice.. Cardiac IR induced PTP opening and mitROS generation, inhibited by SfA. Percent distributions of SCs were significantly affected by IR, and the effects were dependent on the reperfusion time and reversed by SfA and XJB-5-131. TazKD mice demonstrated a 40% lower SC I + III+IV with reduced basal mitochondrial PTP, ROS, and ETC complex activity. Innovation and Conclusion: Sustained reperfusion after cardiac ischemia induces disintegration of mitochondrial SCs, and PTP-induced ROS presumably play a causal role in SC disassembly. Antioxid. Redox Signal. 27, 57-69.

Topics: Animals; Cyclic N-Oxides; Disease Models, Animal; Electron Transport; Female; Lactones; Male; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Reperfusion Injury; Oxidative Stress; Rats; Reactive Oxygen Species; Spiro Compounds

Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppresses the decline of motor performance or improves it, and reduces a graying phenotype in treated HdhQ(150/150) animals relative to matched littermate controls. XJB-5-131 holds promise as a clinical candidate for the treatment of HD.

Topics: Animals; Behavior, Animal; Cells, Cultured; Cyclic N-Oxides; Disease Models, Animal; Huntington Disease; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; Neurons; Oxidative Stress; Weight Loss

The power of microdialysis for in vivo neurochemical monitoring is a result of intense efforts to enhance microdialysis procedures, the probes themselves, and the analytical systems used for the analysis of dialysate samples. Our goal is to refine microdialysis further by focusing attention on what happens when the probes are implanted into brain tissue. It is broadly acknowledged that some tissue damage occurs, such that the tissue nearest the probes is disrupted from its normal state. We hypothesize that mitigating such disruption would refine microdialysis. Herein, we show that the addition of dexamethasone, an anti-inflammatory drug, to the perfusion fluid protects evoked dopamine responses as measured by fast-scan cyclic voltammetry next to the probes after 24 h. We also show that dexamethasone stabilizes evoked dopamine responses measured at the probe outlet over a 4-24 h postimplantation interval. The effects of dexamethasone are attributable to its anti-inflammatory actions, as dexamethasone had no significant effect on two histochemical markers for dopamine terminals, tyrosine hydroxylase and the dopamine transporter. Using histochemical assays, we confirmed that the actions of dexamethasone are tightly confined to the immediate, local vicinity of the probe.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Brain Injuries; Corpus Striatum; Cyclic N-Oxides; Dexamethasone; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Electrochemical Techniques; Functional Laterality; Microdialysis; Nomifensine; Rats; Time Factors; Tyrosine 3-Monooxygenase

Huntington's Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.

Topics: Animals; Cyclic N-Oxides; Disease Models, Animal; Disease Progression; DNA Glycosylases; Female; Huntington Disease; Male; Mice, Inbred C57BL; Mice, Knockout; Trinucleotide Repeat Expansion

Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O(2)) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O(2)). Human disc cells grown at 20% O(2) showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O(2). Importantly, we demonstrated that treatment of accelerated aging Ercc1(-/Δ) mice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1(-/Δ) mice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.

Topics: Adult; Aging; Animals; Cells, Cultured; Cyclic N-Oxides; Disease Models, Animal; Free Radical Scavengers; Glycosaminoglycans; Homeostasis; Humans; Intervertebral Disc Degeneration; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Middle Aged; Mitochondria; Oxidative Stress; Oxygen; Proteoglycans; Reactive Oxygen Species; Tissue Culture Techniques

Oxidative damage and mitochondrial dysfunction are implicated in aging and age-related neurodegenerative diseases, including Huntington's disease (HD). Many naturally occurring antioxidants have been tested for their ability to correct for deleterious effects of reactive oxygen species, but often they lack specificity, are tissue variable, and have marginal efficacy in human clinical trials. To increase specificity and efficacy, we have designed a synthetic antioxidant, XJB-5-131, to target mitochondria. We demonstrate in a mouse model of HD that XJB-5-131 has remarkably beneficial effects. XJB-5-131 reduces oxidative damage to mitochondrial DNA, maintains mitochondrial DNA copy number, suppresses motor decline and weight loss, enhances neuronal survival, and improves mitochondrial function. The findings poise XJB-5-131 as a promising therapeutic compound.

Topics: Animals; Antioxidants; Cell Survival; Cells, Cultured; Cyclic N-Oxides; Disease Models, Animal; DNA Damage; DNA, Mitochondrial; Gene Dosage; Huntington Disease; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; Neurons; Oxidative Stress; Weight Loss