Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function.

Atypical antipsychotics produce severe side effects including myocarditis that may be attributed to oxidative stress. The aim of this study was to investigate the influence of clozapine, ziprasidone, and sertindole on rat heart morphology and determine whether redox imbalane plays a role in development of histopathological changes. Adult 3-month-old male Wistar rats were treated with recommended daily dose for selected drugs. After 4 week treatment histopathological analysis of the heart was performed and expression and activity of antioxidant enzymes determined. All examined drugs induced histopathological changes that were characterized as toxic myocarditis. Degenerative changes in cardiomyocytes were accompanied by lymphocytic infiltration as well as pericardial histopathological alterations in all treated groups. The least prominent changes were observed in sertindole-treated animals, and most severe with clozapine. Clozapine increased superoxide dismutase 1 (SOD1) activity while ziprasidone reduced glutathione reductase (GR) activity. Sertindole exerted no marked effect on antioxidant enzyme function in the heart even though myocardial degeneration was noted. In conclusion, treatment with clozapine or ziprasidone induced pathophysiological alterations in rat heart, which appeared to be associated disturbances in antioxidant capacity. Abbreviation: AAP, Atypical antipsychotics; ROS, reactive oxygen species; SOD1, Copper-zinc superoxide dismutase; SOD2, Manganese superoxide dismutase; CAT, Catalase; GPx, Glutathione peroxidase; GR, Glutathione reductase; H&E, hematoxylin and eosin stain; TNF- α, tumor necrosis factor alpha.

Effects of antipsychotic drug administration on antioxidative defense enzymes in male rat kidney.

The use of atypical antipsychotic drugs (APD) was reported to be associated with adverse effects on the kidneys. Thus, the aim of this study was to examine whether APD exerted their adverse effects by interfering with the renal antioxidant defense system. Male 3-mo-old Wistar rats were treated for 28 d with ziprasidone (ZIP), clozapine (CLO), or sertindole (SER) using a daily dose recommended for antipsychotic drug therapy. The expression and activities of antioxidant enzymes superoxide dismutase (SOD) type 1 and type 2, catalase (CAT), glutathione reductase (GR), and glutathione S-transferases (GSTs) activity were measured in the kidneys. Changes in the kidneys were also evaluated histologically. Ziprasidone, CLO, and SER reduced renal SOD type 1 and type 2 activities. Decreased CAT activity was observed only in SER-treated rats. An inhibition in GR activity and increased activity of GST was found only after treatment with CLO. Histological analysis showed dilatation of proximal tubules in kidneys with all three drugs. In conclusion, data indicate that redox disturbances may contribute to renal morphologic alterations in proximal tubules in rats treated with all APD.

Reactions of superoxide dismutases with HS(-)/H2S and superoxide radical anion: An in vitro EPR study.

Interactions of hydrogen sulfide (HS(-)/H2S), a reducing signaling species, with superoxide dimutases (SOD) are poorly understood. We applied low-T EPR spectroscopy to examine the effects of HS(-)/H2S and superoxide radical anion O2.- on metallocenters of FeSOD, MnSOD, and CuZnSOD. HS(-)/H2S did not affect FeSOD, whereas active centers of MnSOD and CuZnSOD were open to this agent. Cu(2+) was reduced to Cu(1+), while manganese appears to be released from MnSOD active center. Untreated and O2.- treated FeSOD and MnSOD predominantly show 5 d-electron systems, i.e. Fe(3+) and Mn(2+). Our study provides new details on the mechanisms of (patho)physiological effects of HS(-)/H2S.

The relationship of physicochemical properties to the antioxidative activity of free amino acids in Fenton system.

Herein we compared antioxidative activities (AA) of 25 free L-amino acids (FAA) against Fenton system-mediated hydroxyl radical (HO(•)) production in aqueous solution, and examined the relation between AA and a set of physicochemical properties. The rank order according to AA was: Trp > norleucine > Phe, Leu > Ile > His >3,4-dihydroxyphenylalanine, Arg > Val > Lys, Tyr, Pro > hydroxyproline > α-aminobutyric acid > Gln, Thr, Ser > Glu, Ala, Gly, Asn, Asp. Sulfur-containing FAA generated different secondary reactive products, which were discriminated by the means of electron paramagnetic resonance spin-trapping spectroscopy. AA showed a general positive correlation with hydrophobicity. However, when taken separately, uncharged FAA exhibited strong positive correlation of AA with hydrophobicity whereas charged FAA showed negative or no significant correlation depending on the scale applied. A general strong negative correlation was found between AA and polarity. Steric parameters and hydration numbers correlated positively with AA of nonpolar side-chain FAA. In addition, a decrease of temperature which promotes hydrophobic hydration resulted in increased AA. This implies that HO(•)-provoked oxidation of FAA is strongly affected by hydrophobic hydration. Our findings are important for the understanding of oxidation processes in natural and waste waters.

Biotransformation and nitroglycerin-induced effects on antioxidative defense system in rat erythrocytes and reticulocytes.

The effects of nitroglycerin (glyceryl trinitrate - GTN) are mediated by liberated nitric oxide (NO) and formed reactive nitrogen species, which induces oxidative stress during biotransformation in red blood cells (RBCs). The aim of this study was to evaluate effects of GTN on antioxidative defense system (AOS) in rat erythrocytes (without) and reticulocytes (with functional mitochondria). Rat erythrocyte and reticulocyte-rich RBC suspensions were aerobically incubated (2 h, 37°C) without (control) or in the presence of different concentrations of GTN (0.1-1.5 mM). After incubation, concentrations of non-enzymatic components of AOS, activities of antioxidative enzymes and oxidative pentose phosphate (OPP) pathway activity were followed in RBC suspensions. In rat reticulocytes, GTN decreased the activity of mitochondrial MnSOD and increased the activity of CuZnSOD. In rat RBCs, GTN induced increase of Vit E concentration (at high doses), but decreased glutathione content and activities of all glutathione-dependent antioxidative enzymes; the OPP pathway activity significantly increased. GTN biotransformation and induction of oxidative stress were followed by general disbalance of antioxidative capacities in both kinds of RBCs. We suggest that oxidative stress, MnSOD inhibition and depletion of glutathione pool in response to GTN treatment lead to decreased bioavailability of NO after GTN biotransformation in rat reticulocytes.

Effect of atypical antipsychotics on antioxidant enzyme activities in human erythrocytes (in vitro study).

OBJECTIVE: This study was set out to examine the impact of atypical antipsychotic drugs: aripiprazole, clozapine, ziprasidone, olanzapine, quetiapine, sertindole and amisulpride on the activity of antioxidant defence enzymes in human erythrocytes in vitro. METHODS: Cu,Zn-superoxide dismutase (SOD1), catalase (CAT), selenium-dependent glutathione peroxidase and glutathione reductase activities were determined after drugs incubation with blood of 15 apparently healthy non-smoking male volunteers (ages 23-39) for 1 h at 37 °C. RESULTS: A statistically significant increase in SOD1 activity was found in samples incubated with aripiprazole (p < 0.01) and quetiapine (p < 0.05) compared with incubated control. SOD1 activity profile following native polyacrylamide gel electrophoresis indicates that aripiprazole and quetiapine protect enzyme activity from inhibition with hydrogen peroxide. Our results showed that sertindole decreases activity of CAT comparing with control non-treated erythrocytes. Moreover, in sertindole treated erythrocytes, negative correlation between SOD1 and glutathione peroxidase activities was found. Increased amount of hydrogen peroxide in such situation may leave erythrocytes and transform their role in circulation from anti-oxidative to pro-oxidative. CONCLUSIONS: Our results indicate that mechanism through sertindole could express its in vivo toxic effects and point toward possible (neuro)protective effects of aripiprazole and quetiapine.

Stimulative influence of germination and growth of maize seedlings originating from aged seeds by 2,4-D potencies.

BACKGROUND: The 2,4-D (2,4-dichlorophenoxyacetic acid) is using as a growth regulator in tissue culture media. Maize seeds have poor ability to maintain germination rate in the long term. OBJECTIVE: To examine the possible restorative effect of homeopathic 2,4-D potencies on maize seedlings originating from seeds damaged by accelerated aging. METHODS: Seeds of four maize lines were subjected to accelerated aging stress treatment. Seed samples were treated with distilled water (control) and a range of potencies of 2,4-D: 3C, 3.75C, 4.5C, 5.25C and 6C. The germination capacity, fresh substance (FS) and length of root and shoot were determined. Hydrolysis and biosynthesis, GSH/GSSG ratio and redox capacity were calculated. RESULTS: Induced seed aging decreased germination rate and growth of seedlings. 2,4-D potencies did not have a statistically significant effect on germination. However, there were statistically significant effects on FS production, root and shoot length and redox capacity. The 3C potency had the largest effect on the FS accumulation, 4.5C increased root and shoot length, compared to control (statistically significant). The GSH/GSSG ratio and the redox capacity were decreased by aging. The 3C and 4.5C potencies tended to reverse the GSH/GSSG ratio (statistically significant) in the root and shoot, (i.e., shifted the redox balance to the reduced state). CONCLUSION: Homeopathic potencies of 2,4-D appear to have a beneficial effect on artificially aged maize seeds: they stimulate growth through better substance conversion from seed rest, and shift the redox capacity towards a reduced environment. Further work is required to determine if this is an useful means of improving maize seed germination and growth.

The reaction of methionine with hydroxyl radical: reactive intermediates and methanethiol production.

The mechanisms of reaction of methionine with hydroxyl radical are not fully understood. Here, we unequivocally show using electron paramagnetic resonance spin-trapping spectroscopy and GC-FID and GC-MS, the presence of specific carbon-, nitrogen- and sulfur-centered radicals as intermediates of this reaction, as well as the liberation of methanethiol as a gaseous end product. Taking into account the many roles that methionine has in eco- and biosystems, our results may elucidate redox chemistry of this amino acid and processes that methionine is involved in.

Inappropriately chelated iron in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.

ALS is characterized by oxidative damage in the brain and cerebrospinal fluid, which is exerted by pro-oxidative activity of iron. Such activity of iron can be drastically increased in the presence of inappropriate iron ligands that catalyze redox cycling of iron, thereby promoting hydroxyl radical generation. The aim of our study was to determine the relative level of inappropriate iron ligands in the cerebrospinal fluid of ALS patients. To determine the levels of inappropriate iron ligands and redox activity of iron in cerebrospinal fluid (10 samples from ALS patients and 10 controls), we applied electron paramagnetic resonance spectroscopy. We have shown that cerebrospinal fluid of ALS patients comprises two-fold increased level of inappropriate iron ligands, proportionally increasing iron redox activity and hydroxyl radical production compared to controls. In conclusion, our results strongly support the pro-oxidative/detrimental role of inappropriately chelated iron in ALS pathophysiology. The identification of biomolecules that form such iron complexes and their therapeutic targeting may represent the future of ALS treatment.

Oxidative stress and nitrite dynamics under maximal load in elite athletes: relation to sport type.

Maximal workload in elite athletes induces increased generation of reactive oxygen/nitrogen species (RONS) and oxidative stress, but the dynamics of RONS production are not fully explored. The aim of our study was to examine the effects of long-term engagement in sports with different energy requirements (aerobic, anaerobic, and aerobic/anaerobic) on oxidative stress parameters during progressive exercise test. Concentrations of lactates, nitric oxide (NO) measured through stabile end product-nitrites (NO(2) (-)), superoxide anion radical (O(2) (•-)), and thiobarbituric reactive substances (TBARS) as index of lipid peroxidation were determined in rest, after maximal workload, and at 4 and 10th min of recovery in blood plasma of top level competitors in rowing, cycling, and taekwondo. Results showed that sportmen had similar concentrations of lactates and O(2) (•-) in rest. Nitrite concentrations in rest were the lowest in taekwondo fighters, while rowers had the highest levels among examined groups. The order of magnitude for TBARS level in the rest was bicycling > taekwondo > rowing. During exercise at maximal intensity, the concentration of lactate significantly elevated to similar levels in all tested sportsmen and they were persistently elevated during recovery period of 4 and 10 min. There were no significant changes in O(2) (•-), nitrite, and TBARS levels neither at the maximum intensity of exercise nor during the recovery period comparing to the rest period in examined individuals. Our results showed that long term different training strategies establish different basal nitrites and lipid peroxidation levels in sportmen. However, progressive exercise does not influence basal nitrite and oxidative stress parameters level neither at maximal load nor during the first 10 min of recovery in sportmen studied.

Correlation analysis confirms differences in antioxidant defence in the blood of types I and II schizophrenic male patients treated with anti-psychotic medication.

The activities of antioxidant defence enzymes were determined in erythrocytes isolated from types I and II schizophrenic male patients and from healthy controls. Significant differences in superoxide dismutase (SOD) activity (type I: 3284+/-577; type II: 2959+/-697 compared with controls: 3778+/-577; analysis of variance (ANOVA) P<0.001), catalase (CAT) activity (type I: 17.8+/-1.8 compared to type II: 19.2+/-1.5 and both compared with controls: 19.2+/-1.5; ANOVA P<0.05), glutathione peroxidase (GSH-Px) activity (controls: 17.8+/-2.3; type I: 13.9+/-2.9 and type II: 11.6+/-1.9; ANOVA P<0.001) as well as in glutathione reductase (GR) activity (controls: 5,0+/-0.8; type I: 4.3+/-0.9 and type II: 4.5+/-0.8; ANOVA P<0.01) were apparent. Correlation analysis of antioxidant defence enzymes showed significant negative correlation between GSH-Px and CAT activities (P<0.01) in type I patients. In type II patients, GSH-Px activity was significantly positively correlated with GR (P<0.01). Canonical discriminant analysis separated type I and type II patients from controls (and among each other) with a high degree of certainty according to the overall group composition of antioxidant defence enzymes. Our results indicate differences in the composition of antioxidant defence between controls and anti-psychotic treated type I and type II patients with a possible negative feedback influence on the pathological process, which could provide a rationale for applying antioxidants during schizophrenic therapy.

Edaravone May Prevent Ferroptosis in ALS.

Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.

Fructose Consumption Affects Glucocorticoid Signaling in the Liver of Young Female Rats.

The effects of early-life fructose consumption on hepatic signaling pathways and their relation to the development of metabolic disorders in later life are not fully understood. To investigate whether fructose overconsumption at a young age induces alterations in glucocorticoid signaling that might contribute to development of metabolic disturbances, we analysed glucocorticoid receptor hormone-binding parameters and expression of its target genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) and lipid metabolism (lipin-1), as well as redox and inflammatory status in the liver of female rats subjected to a fructose-rich diet immediately after weaning. The fructose diet increased hepatic corticosterone concentration, 11ß-hydroxysteroid dehydrogenase type 1 level, glucocorticoid receptor protein level and hormone-binding activity, as well as lipin-1 level. The expression of glucose-6-phosphatase was reduced in fructose-fed rats, while phosphoenolpyruvate carboxykinase remained unaltered. The fructose-rich diet increased the level of fructose transporter GLUT2, while the expression of fructolytic enzymes fructokinase and aldolase B remained unaltered. The diet also affected pro-inflammatory pathways, but had no effect on the antioxidant defence system. In conclusion, a fructose-rich diet applied immediately after weaning promoted lipogenesis and enhanced hepatic glucocorticoid signaling, possibly to protect against inflammatory damage, but without an effect on gluconeogenesis and antioxidant enzymes. Yet, prolonged treatment might ultimately lead to more pronounced metabolic disturbances.

Effects of protamine sulphate on spontaneous and calcium-induced contractile activity in the rat uterus are potassium channels-mediated.

Protamine sulphate (PS) effect on spontaneous and calcium-induced rhythmic contractions of isolated virgin rat uteri was studied. PS caused dose-dependent relaxation of both types of contractions (two-way ANOVA, significant dose effects). Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; 10(-5) mol/l), methylene blue (MB; 0.9 x 10(-6) mol/l) or propranolol (1.7 x 10(-5) mol/l) enhanced PS-mediated uterine muscle relaxation of spontaneous contractions. Dosedependent relaxation of spontaneous active isolated rat uterus with PS was lower in uteri pretreated with single dose of tetraethylammonium (TEA; 6 x 10(-3) mol/l), glibenclamide (2 x 10(-6) mol/l) and 4-aminopyridine (4-AP; 10(-3) mol/l). Calcium-induced activity of the isolated rat uterus pretreated with the same concentration of L-NAME, MB, or propranolol modified the kinetic of PS-induced relaxation without changes in EC(50) values. Pre-treatment with glibenclamide, TEA and 4-AP significantly reduce PS relaxing effect of calcium-induced activity and according to EC(50) values the order of magnitude was glibenclamide > TEA > 4-AP. PS is mixture of polyamines and may activate different signal-transduction pathways. Our results cleary demonstrate that in uterine smooth muscle PS act dominantly through potassium chanels and marginaly through beta-adrenergic receptos or nitric oxide-dependent pathways.

A Case Report of Exacerbation of Leg Ulcers Associated with Acute High-dose Acetylsalicylic Acid in a Patient with Klinefelter Syndrome.

Klinefelter syndrome (KS) is the most frequent type of congenital sex-chromosomal disorder caused by at least one extra X chromosome and commonly treated with lifetime testosterone therapy. Ulcerative lesions on lower extremities may occur as a complication of KS. The pathogenesis of ulcers in KS patients has not been clarified on a molecular level. Here we present a case of leg ulcers exacerbation associated with the administration of a high dose of acetylsalicylic acid in a 63-year-old KS patient with karyotype 47,XXY undergoing testosterone replacement therapy for the last 20 years. The appearance of the ulcer on the patient's leg occurred during one week of high oral acetylsalicylic acid intake (1.2 g daily). The patient was advised to return to his standard daily dose of 0.1 g of acetylsalicylic acid and significant improvement of his leg ulcer was observed after two weeks. We hypothesize that testosterone-mediated nitric oxide balance in KS patient is perturbed under the condition of acute high-dose acetylsalicylic acid administration. We propose that small standard doses of approximately 0.1 g/day of acetylsalicylic acid have no apparent effect on nitric oxide status, whereas higher doses may cause dysregulation of nitric oxide production and/or utilization, creating conditions which may cause the appearance of leg ulcers in the KS patients.

Effects of carvedilol on left ventricular function and oxidative stress in infants and children with idiopathic dilated cardiomyopathy: a 12-month, two-center, open-label study.

OBJECTIVES: This study was conducted to determine the effects of carvedilol adjunct to standard treatment on left ventricular function (LVF), estimated as ejection fraction (EF) and fractional shortening (FS) on echocardiography, in children with idiopathic dilated cardiomyopathy (DCM). A secondary end point was to characterize the antioxidant potential of carvedilol. METHODS: Hospitalized children aged 62.5 kg) was associated with significant decreases from baseline in systolic BP (130 [4] vs 123 [3] mm Hg; P<0.05), diastolic BP (85 [4] vs 77 [4] mm Hg; P<0.05), and HR (81 [4] vs 65 [4] bpm; P<0.001) after the first month of addition to standard therapy. At 6 months, there were significant improvements from baseline in EF (37.2% [2.4%] vs 50.2% [2.3%]; P<0.001) and FS (18.37% [2.00%] vs 23.58% [0.90%]; P<0.001). Modified NYHAC class was significantly improved in 80% of children (2.9 vs 2.3; P<0.001) at 12 months. The highest dose of carvedilol (0.8 mg/kg/d in children 62.5 kg) was well tolerated in all 21 children. No serious AEs that necessitated study drug discontinuation (tiredness, headache, vomiting) were observed. At baseline, mean (SE) erythrocyte SOD activity (2781 [116] vs 2406 [102] U/g Hb; P<0.05) and GR activity (5.3 [0.3] vs 3.0 [0.2] micromol nicotinamide adenine dinucleotide phosphate [NADPH]/min/g Hb; P<0.001) were significantly higher in children with DCM who received standard therapy compared with healthy controls.CAT activity (12.7[0.9] vs 18.5 [1.0]U/g Hb; P<0.001) was significantly lower, while GSH-Px was unchanged. At 6 and 12 months of therapy, carvedilol plus standard treatment was associated with significant decreases from baseline in SOD (2516 [126] and 2550 [118], respectively, vs 2781 [116] U/g Hb; both, P<0.001) and GR (4.7 [0.3] and 4.1 [0.2], respectively, vs 5.3 [0.2] micromol NADPH/min/g Hb; P<0.05 and P<0.001) and increased CAT (16.9 [1.0] and 16.4 [0.7], respectively, vs 12.7 [0.9] U/g Hb; both, P<0.001). CONCLUSIONS: These pediatric patients with DCM treated for 12 months with carvedilol (up to 0.8 mg/kg/d in children 62.5 kg) were found to have significant improvements in LVF and symptoms of HF. Twelve months of carvedilol therapy was associated with antioxidant enzyme activities near those observed in healthy children.

Can Oxidation-Reduction Potential of Cerebrospinal Fluid Be a Monitoring Biomarker in Amyotrophic Lateral Sclerosis?

The monitoring of progression in amyotrophic lateral sclerosis (ALS) relies on clinical outcome measures that take months to interpret, such as revised ALS functional rating scale (ALSFRS-R) score, with no approved biomarkers. A number of clinical studies have documented the involvement of oxidative stress in ALS pathology. Pertinent to this, we propose to evaluate oxidation-reduction potential (ORP) of cerebrospinal fluid (CSF) as a potential indicator of ALS progression. The case-control study included 24 patients with neurological non-neurodegenerative disorders (controls) and 82 ALS patients with different degrees of disease (ALSFRS-R score: 21-47). ORP was significantly higher in ALS patients than controls. It was not dependent on age or gender. A strong negative correlation was found between ORP and ALSFRS-R score for all patients and patients with spinal onset. In other words, ORP increased with ALS progression. No correlation was found for the subset of patients with bulbar onset, most likely because of the physical distance between neurodegenerative loci and the site of CSF collection. These results lead to the hypothesis that ORP of CSF has a potential as monitoring biomarker in ALS, particularly in the cohort of patients with spinal onset. Antioxid. Redox Signal. 28, 1570-1575.

The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes.

Ibogaine is an indole alkaloid originally extracted from the root bark of the African rainforest shrub Tabernanthe iboga. It has been explored as a treatment for substance abuse because it interrupts drug addiction and relieves withdrawal symptoms. However, it has been shown that ibogaine treatment leads to a sharp and transient fall in cellular ATP level followed by an increase of cellular respiration and ROS production. Since contractile tissues are sensitive to changes in the levels of ATP and ROS, here we investigated an ibogaine-mediated link between altered redox homeostasis and uterine contractile activity. We found that low concentrations of ibogaine stimulated contractile activity in spontaneously active uteri, but incremental increase of doses inhibited it. Inhibitory concentrations of ibogaine led to decreased SOD1 and elevated GSH-Px activity, but doses that completely inhibited contractions increased CAT activity. Western blot analyses showed that changes in enzyme activities were not due to elevated enzyme protein concentrations but posttranslational modifications. Changes in antioxidant enzyme activities point to a vast concentration-dependent increase in H2O2 level. Knowing that extracellular ATP stimulates isolated uterus contractility, while H2O2 has an inhibitory effect, this concentration-dependent stimulation/inhibition could be linked to ibogaine-related alterations in ATP level and redox homeostasis.

Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.

To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (SFE, n = 19), patients in relapse (SR, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between SFE, SR and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in SFE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the SFE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.

Consequences of MnSOD interactions with nitric oxide: nitric oxide dismutation and the generation of peroxynitrite and hydrogen peroxide.

The present study demonstrates that manganese superoxide dismutase (MnSOD) (Escherichia coli), binds nitric oxide (*NO) and stimulates its decay under both anaerobic and aerobic conditions. The results indicate that previously observed MnSOD-catalyzed *NO disproportionation (dismutation) into nitrosonium (NO+) and nitroxyl (NO-) species under anaerobic conditions is also operative in the presence of molecular oxygen. Upon sustained aerobic exposure to *NO, MnSOD-derived NO- species initiate the formation of peroxynitrite (ONOO-) leading to enzyme tyrosine nitration, oxidation and (partial) inactivation. The results suggest that both ONOO- decomposition and ONOO(-)-dependent tyrosine residue nitration and oxidation are enhanced by metal centre-mediated catalysis. We show that the generation of ONOO- is accompanied by the formation of substantial amounts of H2O2. MnSOD is a critical mitochondrial antioxidant enzyme, which has been found to undergo tyrosine nitration and inactivation in various pathologies associated with the overproduction of *NO. The results of the present study can account for the molecular specificity of MnSOD nitration in vivo. The interaction of *NO with MnSOD may represent a novel mechanism by which MnSOD protects the cell from deleterious effects associated with overproduction of *NO.