salicylates and 6-hydroxy-2-5-7-8-tetramethylchroman-2-carboxylic-acid

Oxidative stress has been suggested as a potential contributor to the development of diabetic complications. In this study, we investigated the protective effect of a strong antioxidant copper complex against streptozotocin (STZ)-induced diabetes in animals. Out of four copper complexes used, copper(II) (3,5-diisopropyl salicylate)4 (Cu(II)DIPS) was found to be the most potent antioxidant-copper complex. Pretreatment with Cu(II)DIPS (5 mg/kg) twice a week prior to the injection of streptozotocin (50 mg/kg) has reduced the level of hyperglycemia by 34 % and the mortality rate by 29 %. Injection of the same dosage of the ligand 3,5-diisopropyl salicylate has no effect on streptozotocin-induced hyperglycemia. The same copper complex has neither hypoglycemic activity when injected in normal rats nor antidiabetic activity when injected in STZ-induced diabetic rats. The protective effect of Cu(II)DIPS could be related to its strong antioxidant activity compared to other copper complexes median effective concentration (MEC) = 23.84 μg/ml and to Trolox MEC = 29.30 μg/ml. In addition, it reduced serum 8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative DNA damage, by 29 %. This effect may explain why it was not effective against diabetic rats, when β Langerhans cells were already destroyed. Similar protective activities were reported by other antioxidants like Trolox.

Topics: Animals; Antioxidants; Blood Glucose; Chromans; Coordination Complexes; Copper; Diabetes Mellitus, Experimental; Male; Rats; Rats, Sprague-Dawley; Salicylates

Animals exposed to alcohol during the developmental period develop many physiological and behavioral problems because of neuronal loss in various brain areas including the hypothalamus. Because alcohol exposure is known to induce oxidative stress in developing neurons, we tested whether hypothalamic cells from the fetal brain exposed to ethanol (EtOH) may alter the cell-cell communication between neurons and microglia, thereby leading to increased oxidative stress and the activation of apoptotic processes in the neuronal population in the hypothalamus.. Using enriched neuronal and microglial cells from fetal rat hypothalami, we measured cellular levels of various oxidants (O2 -, reactive oxygen species, nitrite), antioxidants (glutathione [GSH]), antioxidative enzymes (glutathione peroxidase [GSH-Px], catalase, superoxide dismutase) and apoptotic death in neurons in the presence and absence of EtOH or EtOH-treated microglial culture medium. Additionally, we tested the effectiveness of antioxidative agents in preventing EtOH or EtOH-treated microglial conditioned medium actions on oxidative stress and apoptosis in neuronal cell cultures.. Neuronal cell cultures showed increased oxidative stress, as demonstrated by higher cellular levels of oxidants but lower levels of antioxidant and antioxidative enzymes, as well as, increased apoptotic death following treatment with EtOH. These effects of EtOH on oxidative stress and cell death were enhanced by the presence of microglia. Antioxidative agents protected developing hypothalamic neurons from oxidative stress and cellular apoptosis which is caused by EtOH or EtOH-treated microglial culture medium.. These data suggest that exposure of developing hypothalamic neurons to EtOH increases cellular apoptosis via the effects on oxidative stress of neurons directly and via increasing production of microglial-derived factor(s).

Topics: Animals; Antioxidants; Apoptosis; Chromans; Culture Media, Conditioned; Dose-Response Relationship, Drug; Ethanol; Female; Fetus; Hypothalamus; Microglia; Neurons; Organometallic Compounds; Oxidative Stress; Pregnancy; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Salicylates

The effect of doxorubicin on oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) by lactoperoxidase and hydrogen peroxide has been investigated. It was found that: (1) oxidation of ABTS to its radical cation (ABTS*(+)) is inhibited by doxorubicin as evidenced by its induction of a lag period, duration of which depends on doxorubicin concentration; (2) the inhibition is due to doxorubicin hydroquinone reducing the ABTS*(+) radical (stoichiometry 1: 1.8); (3) concomitant with the ABTS*(+) reduction is oxidation of doxorubicin; only when the doxorubicin concentration decreases to a near zero level, net oxidation of ABTS could be detected; (4) oxidation of doxorubicin leads to its degradation to 3-methoxysalicylic acid and 3-methoxyphthalic acid; (5) the efficacy of doxorubicin to quench ABTS*(+) is similar to the efficacy of p-hydroquinone, glutathione and Trolox C. These observations support the assertion that under certain conditions doxorubicin can function as an antioxidant. They also suggest that interaction of doxorubicin with oxidants may lead to its oxidative degradation.

Topics: Antibiotics, Antineoplastic; Benzothiazoles; Chromans; Doxorubicin; Free Radicals; Glutathione; Hydrogen Peroxide; Hydroquinones; Lactoperoxidase; Oxidants; Oxidation-Reduction; Phthalic Acids; Salicylates; Sulfonic Acids; Thiazoles

Diets high in polyunsaturated fatty acids (PUFA) are important for the development of alcoholic liver injury. The goal of this report was to characterize toxicity by arachidonic acid (AA), its enhancement by salicylate, and the role of mitochondrial injury in the pathway leading to toxicity in hepatocytes from pyrazole-treated rats. AA caused toxicity that was increased by sodium salicylate. This synergistic toxicity was reduced by diallyl sulfide (DAS), an inhibitor of CYP2E1; Trolox ([+/-] 6-hydroxy, 2, 5, 7, 8-tetramethylchroman-2-carboxylic acid), an inhibitor of lipid peroxidation; Z-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD-FMK), a pan caspase inhibitor; and by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition. Mitochondrial membrane potential also was reduced, and this was prevented by cyclosporine, diallyl sulfide, and Trolox. There was release of mitochondrial cytochrome c into the cytosol and activation of caspase 3, which were prevented by cyclosporine, diallylsulfide, and Trolox. Toxicity was prevented by expression of catalase either in the cytosolic or the mitochondrial compartment. Levels of CYP2E1 rapidly declined, and this was partially prevented by salicylate. These results are consistent with a model in which CYP2E1-dependent production of reactive oxygen species enhances lipid peroxidation when AA is added to hepatocytes. This results in damage to the mitochondria, with initiation of a membrane permeability transition and a decline in membrane potential, followed by release of cytochrome c, caspase 3 activation, and cellular toxicity. In conclusion, damage to mitochondria appears to play an important role in the CYP2E1 plus AA toxicity.

Topics: Adenosine Triphosphate; Allyl Compounds; Animals; Antioxidants; Apoptosis; Arachidonic Acid; Caspase 3; Caspase Inhibitors; Caspases; Catalase; Cells, Cultured; Chromans; Cyclooxygenase Inhibitors; Cyclosporine; Cytochrome c Group; Cytochrome P-450 CYP2E1; Cytosol; Drug Synergism; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hepatocytes; Lipid Peroxidation; Male; Membrane Potentials; Mitochondria; Rats; Rats, Sprague-Dawley; Salicylates; Sulfides

Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical (8OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an *OH scavenger, was used to detect the in vitro generation of *OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.

Topics: Antioxidants; Ascorbic Acid; Chromans; Dopamine; Dose-Response Relationship, Drug; Hydroxybenzoates; Hydroxyl Radical; Iron; Melatonin; Oxidation-Reduction; Salicylates; Selegiline

Ochratoxin A, ochratoxin alpha (its major metabolite in rodents) and seven structurally related substances were assayed for SOS DNA repair inducing activity in Escherichia coli PQ37 strain. At a concentration range of 0.1-4 mM, ochratoxin A, chloroxine, 5-chloro-8-quinolinol, 4-chloro-meta-cresol and chloroxylenol were found to induce SOS-DNA repair in the absence of an exogenous metabolic activation system. Ochratoxin B, ochratoxin alpha, 5-chlorosalicylic acid and citrinin were inactive, but all except ochratoxin alpha were cytotoxic. Thus, the presence of a chlorine at C-5 in ochratoxin A and in other analogues appears to be one determinant of their genotoxicity. In order to ascertain whether this reactivity involves a bacterial glutathione conjugation reaction, we investigated the modifying effect on the genotoxicity of ochratoxin A of amino oxyacetic acid, an inhibitor of cysteine conjugate beta-lyase. Amino oxyacetic acid decreased the cytotoxicity of ochratoxin A but did not alter its genotoxic activity, suggesting the formation of a cytotoxic thiol-containing derivative. The way in which ochratoxin A and some of its active analogues induce SOS DNA repair activity was further investigated in E. coli PQ37 and in three derived strains (PQ300, OG100 and OG400, containing deletions within the oxy R regulon). The response in PQ37 strain was measured in the absence and presence of Trolox C, a hydrosoluble form of vitamin E. Trolox C completely quenched the genotoxicity of ochratoxin A, which was no greater in mutated than in wild type strains. These results implicate an ochratoxin A-derived free radical rather than reduced oxygen species as genotoxic intermediate(s) in bacteria.

Topics: Aminooxyacetic Acid; Chloroquinolinols; Chromans; Citrinin; Cresols; Dimethyl Sulfoxide; Escherichia coli; Free Radicals; Glutathione; Mutagenicity Tests; Ochratoxins; Salicylates; SOS Response, Genetics; Stimulation, Chemical; Structure-Activity Relationship; Xylenes