ubiquinol and Disease-Models--Animal

Coenzyme Q(10) is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ(10) deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ(10). It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ(10) deficiency can also be observed in patients with defects unrelated to CoQ(10) biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.Patients with both primary and secondary deficiencies benefit from high-dose oral supplementation with CoQ(10). In primary forms treatment can stop the progression of both SRNS and encephalopathy, hence the critical importance of a prompt diagnosis. Treatment may be beneficial also for secondary forms, although with less striking results.In this review we will focus on CoQ(10) biosynthesis in humans, on the genetic defects and the specific clinical phenotypes associated with CoQ(10) deficiency, and on the diagnostic strategies for these conditions.

Topics: Adenosine Triphosphate; Animals; Ataxia; Central Nervous System Diseases; Disease Models, Animal; Electron Transport; Humans; Mice; Mitochondria; Mitochondrial Diseases; Muscle Weakness; Nephrotic Syndrome; Oxidative Stress; Phenotype; Ubiquinone

Topics: Animals; Disease Models, Animal; Female; Magnesium; Mice; Pharmaceutical Preparations; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; Sphingomyelin Phosphodiesterase; Ubiquinone

The cardioprotective effect of ubiquinol on the model of myocardium reperfusion injury in rats was investigated. The study was carried out using mature males of outbred rats. Myocardial ischemia-reperfusion injury was performed after 30-minute ligation of the left coronary artery followed by reperfusion. The main criteria for assessing the development of pathology included the results of electrocardiography, biochemical analysis of blood plasma, histological and histochemical study of the myocardium. Development of the reperfusion damage of the myocardium caused specific changes in non-treated animals. The best therapeutic effect on biochemical indices was provided by a drug with the known cardioprotective activity - Mexidolâ and the tested object ubiquinol at doses of 2-6 mg/kg. Evaluation of the results of electrocardiography allowed to confirm the development of ischemic myocardial damage in all groups. The results of histochemical and histological examination of the myocardium suggest a high cardioprotective activity of ubiquinol at a dose of 3 mg/kg and a potential cardioprotective effect of ubiquinol in doses closest to the therapeutic doses of 2 and 6 mg/kg. Ubiquinol is a dose 9 mg/kg showed signs of prooxidant activity, manifested in the form of aggravation of reperfusion injury of the myocardium. The most effective in the conditions of experimental pathology is 1% solution of ubiquinol, at a dose of 3 mg/kg, whose cardioprotective effect is comparable or higher than that for the reference drug Mexidolâ at the therapeutic dose. In doses that are greater than therapeutic ubiquinol is able to act as a pro-oxidant.. V stat'e predstavleny rezul'taty éksperimental'nogo doklinicheskogo issledovaniia, tsel'iu kotorogo iavlialas' otsenka kardioprotektornogo deĭstviia 1% rastvora ubikhinola pri vnutrivennom vvedenii v usloviiakh éksperimental'nogo reperfuzionnogo povrezhdeniia miokarda krys. Issledovanie provodilos' s ispol'zovaniem polovozrelykh samtsov autbrednykh krys, modelirovanie ishemii-reperfuzii miokarda osushchestvlialos' putem 30-minutnogo ligirovaniia levoĭ koronarnoĭ arterii s posleduiushcheĭ reperfuzieĭ. V kachestve kriteriev otsenki razvitiia patologii ispol'zovali rezul'taty élektrokardiografii, biokhimicheskogo analiza plazmy krovi, gistologicheskoe i gistokhimicheskoe issledovanie miokarda. Na fone razvitiia reperfuzionnogo povrezhdeniia miokarda razvivalis' kharakternye priznaki ishemii miokarda u zhivotnykh, ne poluchavshikh lechenie. Nailuchshiĭ terapevticheskiĭ éffekt v otnoshenii biokhimicheskikh pokazateleĭ okazali standartnyĭ ob"ekt Meksidolâ i testiruemyĭ ob"ekt Ubikhinol v dozakh 2-6 mg/kg. Otsenka rezul'tatov élektrokardiografii vo vtorom standartnom otvedenii pozvolila podtverdit' razvitie ishemicheskogo povrezhdeniia miokarda vo vsekh gruppakh. Rezul'taty gistokhimicheskogo i gistologicheskogo issledovaniia miokarda pozvoliaiut sdelat' vyvod o vysokoĭ kardioprotektornoĭ aktivnosti ubikhinola v doze 3 mg/kg i potentsial'nom kardioprotektornom éffekte ubikhinola v dozakh, naibolee blizkikh k terapevticheskoĭ – 2 i 6 mg/kg. Ubikhinol v doze 9 mg/kg proiavil priznaki prooksidantnoĭ aktivnosti, proiavivshiesia v vide usugubleniia razvitiia reperfuzionnogo porazheniia miokarda. Naibolee éffektivnymi v usloviiakh éksperimental'noĭ patologii iavliaetsia preparat ubikhinol, 1% rastvor, v doze 3 mg/kg, kardioprotektornyĭ éffekt kotorogo sopostavim, libo prevyshaet takovoĭ dlia referentnogo preparata Meksidolâ v terapevticheskoĭ doze. V dozakh, mnogokratno prevyshaiushchikh terapevticheskuiu, ubikhinol sposoben vystupat' v roli prooksidanta.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Heart; Male; Myocardial Reperfusion Injury; Myocardium; Rats; Ubiquinone

Topics: Animals; Antioxidants; Apoptosis; Astrocytes; bcl-2-Associated X Protein; bcl-Associated Death Protein; bcl-X Protein; Caspase 3; Cell Survival; Disease Models, Animal; Female; Gene Expression Regulation; Intraocular Pressure; Mice; Mice, Inbred C57BL; Microglia; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Reperfusion Injury; Retinal Degeneration; Retinal Ganglion Cells; Signal Transduction; Ubiquinone

Topics: Animals; Autophagy; Blotting, Western; Cell Survival; Disease Models, Animal; Flow Cytometry; Mice; Mitochondria, Muscle; Mitochondrial Diseases; Oxidative Stress; Physical Conditioning, Animal; Ubiquinone

Accelerating wound healing after tooth extraction is beneficial in dental treatment. Application of antioxidants, such as reduced coenzyme Q10 (rCoQ10), may promote wound healing after tooth extraction. In this study, we examined the effects of topical application of rCoQ10 on wound healing after tooth extraction in rats. After maxillary first molars were extracted, male Fischer 344 rats (8 weeks old) (n = 27) received topical application of ointment containing 5% rCoQ10 (experimental group) or control ointment (control group) to the sockets for 3 or 8 days (n = 6-7/group). At 3 days after extraction, the experimental group showed higher collagen density and lower numbers of polymorphonuclear leukocytes in the upper part of socket, as compared to the control group (p < 0.05). Gene expression of interleukin-1β, tumor necrosis factor-α and nuclear factor-κB were also lower in the experimental group than in the control group (p < 0.05). At 8 days after tooth extraction, there were no significant differences in collagen density, number of polymorphonuclear leukocytes and bone fill between the groups. Our results suggest that topical application of rCoQ10 promotes wound healing in the soft tissue of the alveolar socket, but that rCoQ10 has a limited effect on bone remodeling in rats.

Topics: Animals; Antioxidants; Bone and Bones; Bone Remodeling; Collagen; Disease Models, Animal; Imaging, Three-Dimensional; Interleukin-1beta; Male; Neutrophils; NF-kappa B; Ointments; Pilot Projects; Rats; Rats, Inbred F344; Tooth Extraction; Tumor Necrosis Factor-alpha; Ubiquinone; Wound Healing

Oxidative stress and mitochondrial impairment are the main pathogenic mechanisms of Amyotrophic Lateral Sclerosis (ALS), a severe neurodegenerative disease still lacking of effective therapy. Recently, the coenzyme-Q (CoQ) complex, a key component of mitochondrial function and redox-state modulator, has raised interest for ALS treatment. However, while the oxidized form ubiquinone10 was ineffective in ALS patients and modestly effective in mouse models of ALS, no evidence was reported on the effect of the reduced form ubiquinol10, which has better bioavailability and antioxidant properties. In this study we compared the effects of ubiquinone10 and a new stabilized formulation of ubiquinol10 on the disease course of SOD1(G93A) transgenic mice, an experimental model of fALS. Chronic treatments (800 mg/kg/day orally) started from the onset of disease until death, to mimic the clinical trials that only include patients with definite ALS symptoms. Although the plasma levels of CoQ10 were significantly increased by both treatments (from <0.20 to 3.0-3.4 µg/mL), no effect was found on the disease progression and survival of SOD1(G93A) mice. The levels of CoQ10 in the brain and spinal cord of ubiquinone10- or ubiquinol10-treated mice were only slightly higher (≤10%) than the endogenous levels in vehicle-treated mice, indicating poor CNS availability after oral dosing and possibly explaining the lack of pharmacological effects. To further examine this issue, we measured the oxidized and reduced forms of CoQ9/10 in the plasma, brain and spinal cord of symptomatic SOD1(G93A) mice, in comparison with age-matched SOD1(WT). Levels of ubiquinol9/10, but not ubiquinone9/10, were significantly higher in the CNS, but not in plasma, of SOD1(G93A) mice, suggesting that CoQ redox system might participate in the mechanisms trying to counteract the pathology progression. Therefore, the very low increases of CoQ10 induced by oral treatments in CNS might be not sufficient to provide significant neuroprotection in SOD1(G93A) mice.

Topics: Amyotrophic Lateral Sclerosis; Animals; Brain; Central Nervous System; Disease Models, Animal; Disease Progression; Humans; Mice; Mice, Transgenic; Spinal Cord; Superoxide Dismutase; Ubiquinone

Mitochondrial disorders are often associated with primary or secondary CoQ10 decrease. In clinical practice, Coenzyme Q10 (CoQ10) levels are measured to diagnose deficiencies and to direct and monitor supplemental therapy. CoQ10 is reduced by complex I or II and oxidized by complex III in the mitochondrial respiratory chain. Therefore, the ratio between the reduced (ubiquinol) and oxidized (ubiquinone) CoQ10 may provide clinically significant information in patients with mitochondrial electron transport chain (ETC) defects. Here, we exploit mutants of Caenorhabditis elegans (C. elegans) with defined defects of the ETC to demonstrate an altered redox ratio in Coenzyme Q9 (CoQ9), the native quinone in these organisms. The percentage of reduced CoQ9 is decreased in complex I (gas-1) and complex II (mev-1) deficient animals, consistent with the diminished activity of these complexes that normally reduce CoQ9. As anticipated, reduced CoQ9 is increased in the complex III deficient mutant (isp-1), since the oxidase activity of the complex is severely defective. These data provide proof of principle of our hypothesis that an altered redox status of CoQ may be present in respiratory complex deficiencies. The assessment of CoQ10 redox status in patients with mitochondrial disorders may be a simple and useful tool to uncover and monitor specific respiratory complex defects.

Topics: Animals; Antioxidants; Caenorhabditis elegans; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Humans; Mitochondria; Mitochondrial Diseases; Oxidation-Reduction; Ubiquinone

Oxygen/nitrogen reactive species (ROS/RNS) are currently implicated in the pathogenesis of ulcerative colitis, drawing attention on the potential prophylactic and healing properties of antioxidants, scavengers, chelators. We evaluated the possible protective/curative effects of a natural antioxidant preparation based on Aloe vera and ubiquinol, against intestinal inflammation, lesions, and pathological alterations of the intestinal electrophysiological activity and motility, in a rat model of DSS-induced colitis. 5% dextrane sulfate (DDS) (3 days), followed by 1% DSS (4 days) was administered in drinking water. The antioxidant formulation (25 mg/kg) was delivered with a pre-treatment protocol, or simultaneously or post-colitis induction. Spontaneous and acetylcholine-stimulated electrical activity were impaired in the small intestine and in distal colon, upon exposure to DSS only. Severe inflammation occurred, with increased myeloperoxidase activity, and significant alterations of the oxidant/antioxidant status in colonic tissue and peritoneal cells. Lipoperoxidation, superoxide production, glutathione peroxidase and glutathione-S-transferase activities, and reduced glutathione content increased, whilst superoxide dismutase and catalase activities were sharply suppressed in colon tissue. ROS/RNS formation in peritoneal cells was strongly inhibited. Inflammation, electrical/mechanical impairment in the gut, and a great majority of oxidative stress parameters were improved substantially by pre-treatment with the antioxidant preparation, but not by simultaneous administration or post-treatment.

Topics: Acetylcholine; Aloe; Animals; Antioxidants; Catalase; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Electrophysiology; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Intestine, Small; Lipid Peroxidation; Male; Muscle, Smooth; Rats; Rats, Wistar; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Ubiquinone