[Natalizumab and reduction of carbonylated proteins in patients with multiple sclerosis]. / Natalizumab y reduccion de los niveles de proteinas carboniladas en pacientes con esclerosis multiple.

INTRODUCTION: The sensitivity of the central nervous system to oxidative damage and its relationship with inflammatory response are well known. Recent studies have shown that oxidative stress is present in the establishment and development of multiple sclerosis (MS). One of the most recent treatments in this process is natalizumab, a monoclonal antibody. AIM: To evaluate whether the therapeutic effect of natalizumab is associated with the severity of the disease and the oxidative damage. PATIENTS AND METHODS: Researchers recruited twenty patients with relapsing-remitting MS (RRMS) undergoing therapy with natalizumab and distributed, according to the Expanded Disability Status Scale (EDSS), in two groups: RRMS-1 (EDSS < 5) and RRMS-2 (EDSS ≥ 5). Blood samples were taken for an oxidative profile study. RESULTS: Data showed a decrease in carbonylated proteins following treatment with natalizumab. The reduction in oxidative damage rated as protein oxidation is significant between the previous (baseline) situation of the patient and after 14 months' treatment. The most significant decrease coincided with the patients with the highest levels of severity in the process. Although it has not been possible to establish a correlation, the statistical significance is higher for patients in the RRMS-2 group treated with natalizumab. The antioxidant systems, on the other hand, did not display any statistically significant changes. CONCLUSIONS: Natalizumab brings about a reduction in carbonylated protein levels.

Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington's disease rat model: effects on neurotrophic factors and neuronal density.

There is evidence to suggest that the neuroprotective effect of exposure of extremely low-frequency electromagnetic fields (ELF-EMF) may be due, at least in part, to the effect of these fields on neurotrophic factors levels and cell survival, leading to an improvement in behavior. This study was undertaken to investigate the neuroprotective effects of ELFEF in a rat model of 3-nitropropionic acid (3NP)-induced Huntington's disease. Behavior patterns were evaluated, and changes in neurotrophic factor, cell damage, and oxidative stress biomarker levels were monitored in Wistar rats. Rats were given 3NP over four consecutive days (20 mg/kg body weight), whereas ELFEF (60 Hz and 0.7 mT) was applied over 21 days, starting after the last injection of 3NP. Rats treated with 3NP exhibited significantly different behavior in the open field test (OFT) and the forced swim test (FST), and displayed significant differences in neurotrophic factor levels and oxidative stress biomarkers levels, together with a neuronal damage and diminished neuronal density, with respect neuronal controls. ELFEF improved neurological scores, enhanced neurotrophic factor levels, and reduced both oxidative damage and neuronal loss in 3NP-treated rats. ELFEF alleviates 3NP-induced brain injury and prevents loss of neurons in rat striatum, thus showing considerable potential as a therapeutic tool.

Olive oil reduces oxidative damage in a 3-nitropropionic acid-induced Huntington's disease-like rat model.

Free radicals contribute to altered neuronal functions in neurodegenerative diseases and brain aging, by producing lipid- and other molecule-dependent modifications. The Mediterranean diet has been associated with a reduced risk of neurodegenerative disease. This study sought to verify whether extra-virgin olive oil (EVOO) exerted a brain antioxidant effect, protecting the brain against the oxidative stress caused by 3-nitropropionic acid (3NP). 3NP was administered intraperitoneally (i.p.) at a dose of 20 mg/kg body weight over four consecutive days. EVOO (representing 10% of calorie intake in the total standard daily diet of rats) and hydroxytyrosol (HT; 2.5 mg/kg body weight) were administered for 14 days. In all studied samples, 3NP caused a rise in lipid peroxides (LPO) and a reduction in glutathione (GSH) content. While the results showed that EVOO and HT reduces lipid peroxidation product levels and blocks the GSH depletion prompted by 3NP in both striatum and rest of the brain in Wistar rats. In addition, EVOO blocks and reverses the effect of 3NP on succinate dehydrogenase activity. In brief, the data obtained indicate that EVOO and HT act as a powerful brain antioxidant.

Cardiorespiratory fitness and oxidative stress: effect of acute maximal aerobic exercise in children and adolescents.

AIM: Evaluate the effects of oxidative stress in saliva in young males, according to their cardiorespiratory fitness and taking acute maximal aerobic exercise into consideration. An incremental exercise test (20 meter shuttle run) was used. METHODS: Seventy healthy male subjects, aged 10 to 14 years, were included in the study and were classified into two groups according to fitness parameters. Subjects were expected to take the 20 meter shuttle run test. RESULTS: Group I had high cardiorespiratory fitness while group II had low cardiorespiratory fitness below the mean for their age. Saliva samples were taken before and immediately after exercise in order to measure levels of reduced glutathione, lipoperoxides, glutathione/lipoperoxides ratio and catalase. The values of reduced glutathione were significantly diminished regardless the subjects' cardiorespiratory fitness. The glutathione/lipoperoxides ratio was significantly diminished in group I. In addition, positive correlations were observed between lipoperoxides values after the 20 meter shuttle run test. CONCLUSION: High cardiorespiratory fitness does not seem to be an essential factor effecting in the oxidative stress values before exercise. However, oxidative stress could be greater with more intensity and duration after and acute maximal physical exercise.

Mice lacking the peroxisome proliferator-activated receptor α gene present reduced number of dopamine neurons in the substantia nigra without altering motor behavior or dopamine neuron decline over life.

Peroxisome proliferator-activated receptor alpha (PPAR-α), which is expressed by neurons of the nigrostriatal circuit, plays a prominent role in oxidative stress and neuroinflammation. The objectives were: (i) to discern if levels of antioxidant molecules and pro-inflammatory cytokines, along with PPAR-γ expression are modified in the nigrostriatal region of null PPAR-α mice, (ii) to discern whether dopaminergic neuronal features of the substantia nigra pars compacta (SNpc) and dorsal striatum are affected in null mice, and (iii) to establish if aging-induced decline of nigral neurons is different in null PPAR-α mice relative to wild-type littermates. A substantial decrease in antioxidant molecules was found in SNpc of null mice, by using ELISA. The pro-inflammatory factors TNF-α and IL-3 were found to be reduced in the substantia nigra, suggesting dual and opposite effects of PPAR-α deficiency on oxidative and pro-inflammatory molecules. Immunohistological and stereological studies revealed that young null mice present a smaller SNpc (-19.8%; TH downregulation was discarded). Normal locomotion in an open-field was not affected in null mice. Dopamine cell death could be caused by reduced protection against oxidative stress. Old null mice showed a percentage reduction of nigral dopamine neurons similar to that of young null animals, with a rate of decline over life of around 44%, the same value than that of wild-type littermates. These findings suggest that nuclear PPAR-α is necessary for the normal development of the substantia nigra along with normal levels of antioxidant molecules. Lack of PPAR-α does not modify the normal motor behavior of mice or decline of nigral dopamine neurons throughout life.

Olfactory bulbectomy induced oxidative and cell damage in rat: protective effect of melatonin.

In this study we analyzed the effects of melatonin (Mel, 1 mg/kg ip) on behavioral changes as well as cell and oxidative damage prompted by bilaterally olfactory bulbectomy. Olfactory bulbectomy caused an increase in lipid peroxidation products and caspase-3, whereas it prompted a decrease of reduced glutathione (GSH) content and antioxidative enzymes activities. Additionally, olfactory bulbectomy induced behavioral changes characterized by the enhancement of immobility time in the forced swim test and hyperactivity in the open field test. All these changes were normalized by treatment of Mel (14 days). Our data show that Mel has a beneficial neuropsychiatric action against oxidative stress, cell damage and behavior alterations.

[The molecular bases of Huntington's disease: the role played by oxidative stress]. / Bases moleculares de la enfermedad de Huntington: papel del estrés oxidativo.

INTRODUCTION: Huntington's disease is a neurodegenerative, autosomal dominant disease that mainly affects the basal ganglia. The disorder is caused by mutation in the gene encoding the huntingtin protein (Htt), producing intracellular aggregates. The adult form (chorea with dementia) is the most frequent. It is characterized by unpredictable, spasmodic, involuntary and constant movements, mostly associated with psychiatric and cognitive alterations. DEVELOPMENT: The main characteristics of Huntington's disease are: neuronal loss, glyosis, and accumulations of mutated Htt, all associated with different underlying channels in the pathogenesis of the disease, such as: excitotoxicity, energy deficit (ATP depletion), reduction in the synthesis and release of neurotrophic factors (BDNF and GDNF), and oxidative stress. Oxidative stress is involved in the pathogenesis of various neurodegenerative diseases, including Huntington's disease, and numerous studies have shown the existence of oxidative damage in the plasma and tissue of patients suffering from this disease. CONCLUSIONS: Oxidative stress in patients with Huntington's disease may be used as an evolutionary-prognostic marker of both the disease and therapeutic effectiveness, as well as an interesting field of research for the development of new therapeutic strategies.

Bases moleculares de la enfermedad de Huntington: papel del estrés oxidativo / The molecular bases of Huntington’s disease: the role played by oxidative stress

Introducción. La enfermedad de Huntington es un proceso de naturaleza neurodegenerativa, autosómica dominante,que afecta principalmente a los ganglios de la base. Está causada por mutación en el gen que codifica para la proteínahuntingtina (Htt), originando agregados intracelulares. La forma adulta, coreica y con demencia es la más frecuente. Cursacon movimientos impredecibles, espasmódicos, involuntarios y constantes, en la mayoría de los casos asociados a alteracionespsiquiátricas y cognitivas. Desarrollo. La enfermedad de Huntington se caracteriza principalmente por pérdida neuronal,gliosis y acúmulos de Htt mutada, todo ello asociado a diferentes vías subyacentes en la patogénesis, como son, entre otras,excitotoxicidad, déficit energético (depleción de adenosín trifosfato), reducción en la síntesis y liberación de factores neurotróficos(factor neurotrófico derivado del cerebro y factor neurotrófico derivado de una línea celular glial), y estrés oxidativo.El estrés oxidativo está involucrado en la patogénesis de varias enfermedades neurodegenerativas, entre ellas la enfermedad de Huntington, y son varios los estudios que muestran la existencia de daño oxidativo en el plasma y el tejido de estos pacientes.Conclusiones. El estrés oxidativo acontecido en la enfermedad de Huntington puede utilizarse como marcador de evolución- pronóstico de la enfermedad y de efectividad terapéutica, y es un foco de interés para el desarrollo de nuevas estrategias terapéuticas (AU)

Introduction. Huntington’s disease is a neurodegenerative, autosomal dominant disease that mainly affects thebasal ganglia. The disorder is caused by mutation in the gene encoding the huntingtin protein (Htt), producing intracellularaggregates. The adult form (chorea with dementia) is the most frequent. It is characterized by unpredictable, spasmodic,involuntary and constant movements, mostly associated with psychiatric and cognitive alterations. Development. The maincharacteristics of Huntington’s disease are: neuronal loss, glyosis, and accumulations of mutated Htt, all associated withdifferent underlying channels in the pathogenesis of the disease, such as: excitotoxicity, energy deficit (ATP depletion),reduction in the synthesis and release of neurotrophic factors (BDNF and GDNF), and oxidative stress. Oxidative stress isinvolved in the pathogenesis of various neurodegenerative diseases, including Huntington’s disease, and numerous studieshave shown the existence of oxidative damage in the plasma and tissue of patients suffering from this disease. Conclusions.Oxidative stress in patients with Huntington’s disease may be used as an evolutionary-prognostic marker of both the diseaseand therapeutic effectiveness, as well as an interesting field of research for the development of new therapeutic strategies (AU)

Neuroprotective effect of carvedilol and melatonin on 3-nitropropionic acid-induced neurotoxicity in neuroblastoma

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In neurodegenerative diseases, progressive oxidative stress is a major event that precedes neuronal death. Oxidative stress is characterized by an imbalance between oxidants and antioxidants. This imbalance induced oxidative molecular and cell damage, reducing cellular viability. 3-Nitropropionic acid (3NP) causes oxidative stress and other molecular and cellular changes similar to those observed in neurons of patients with Huntington’s disease. Since carvedilol and melatonin act as free-radical scavengers, this study examined the effect of carvedilol (10−5 M) and melatonin (10−5 M) on oxidative and cell damage induced by 3NP in N1E-115 neuroblastoma cells. Carvedilol and melatonin prevented the increases in lipid peroxidation and total LDH activity, as well as the depletion of reduced glutathione (GSH) and the reduction of antioxidative enzymes activities in N1E-115 cells incubated with 100 mM 3NP. All these carvedilol and melatonin effects were more intense when the drugs were added before rather than after inducing the damage by 3NP. These results also provided evidence supporting the hypothesis that carvedilol and melatonin can be useful for treating neurodegenerative diseases, such as Huntington’s disease (AU)

Effect of melatonin on myocardial oxidative stress induced by experimental obstructive jaundice.

OBJECTIVE: melatonin has been demonstrated to have active antioxidant properties in different tissues during experimental cholestasis. The aim of this research was to study myocardial oxidative stress on obstructive jaundice, and to analyze the effect of melatonin on myocardial oxidative lesions. MATERIAL AND METHODS: we achieved cholestasis by ligature and sectioning of the main bile duct. Melatonin was administered intraperitoneally (500 microg/kg/day). We measured malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxydase (GPx) antioxidant enzyme levels in the heart tissue. RESULTS: obstructive cholestasis increased MDA and decreased GSH as well as all antioxidant enzymes. Melatonin administration significantly decreased MDA values, and increased GSH and antioxidant enzymes on the icteric animal myocardium. CONCLUSIONS: melatonin treatment prevents oxidative stress in the cardiac tissue as induced by experimental cholestasis.

Effect of melatonin on myocardial oxidative stress induced by experimental obstructive jaundice

Objective: melatonin has been demonstrated to have activeantioxidant properties in different tissues during experimentalcholestasis. The aim of this research was to study myocardial oxidativestress on obstructive jaundice, and to analyze the effect ofmelatonin on myocardial oxidative lesions.Material and methods: we achieved cholestasis by ligatureand sectioning of the main bile duct. Melatonin was administeredintraperitoneally (500 ìg/kg/day). We measured malondialdehyde(MDA), reduced glutathione (GSH), catalase (CAT), superoxidedismutase (SOD) and glutathione peroxydase (GPx) antioxidantenzyme levels in the heart tissue.Results: obstructive cholestasis increased MDA and decreasedGSH as well as all antioxidant enzymes. Melatonin administrationsignificantly decreased MDA values, and increased GSH and antioxidantenzymes on the icteric animal myocardium.Conclusions: melatonin treatment prevents oxidative stressin the cardiac tissue as induced by experimental cholestasis(AU)

Cambios en biomarcadores del estrés oxidativo inducidos por la pubertad / Changes in oxidative stress biomarkers induced by puberty

Objetivos: Estudiar la influencia del estrés oxidativo (EO) en la adolescencia, dado que éste se produce por un desequilibrio entre sustancias oxidantes y mecanismos de defensa antioxidante y se ha descrito como uno de los factores que más influye en la disminución progresiva de las funciones biológicas con el avance de la edad. Material y métodos: Se han seleccionado 38 varones prepúberes con estadio de Tanner G1-P1 y 32 varones púberes sanos con estadio de Tanner G3−4-P3−4 de 10 a 14 años, que presentaban peso, talla, índice de masa corporal, frecuencia cardíaca y presión arterial en el percentil 50 de su edad (desviación estándar ±1). Se midieron en saliva las concentraciones basales de los productos de lipoperoxidación, glutatión reducido y catalasa, ya que se ha demostrado una buena correlación entre las concentraciones plasmáticas y salivares de los biomarcadores del EO. Resultados: Los varones puberales presentaron concentraciones superiores significativas de los productos de lipoperoxidación (p<0,001), no se obtuvieron diferencias significativas en los demás biomarcadores estudiados. Se encontró una correlación significativa positiva entre los productos de lipoperoxidación y el glutatión reducido (p<0,001). Conclusión: Se describe por primera vez que en la pubertad hay un aumento de los productos de lipoperoxidación y que podrían estar influyendo en la aparición de EO en esta etapa de la vida (AU)

Aim: Evaluate the influence of puberty in oxidative stress. Subjects and methods: The study included 38 prepubescent males with Tanner G1-P1 and 32 healthy pubescent boys with Tanner G3−4-P3−4. Weight, height and body mass index, heart rate, blood pressure values were within the 50 percentile 50±1SD for their age. The biomarkers were measured in saliva, as a good correlation between saliva and plasma levels has been reported in lipoperoxidation products, reduced glutathione and catalase. Results: Pubescent boys had significantly higher levels of lipoperoxidation products (P<0.001) compared with the prepubertal group, with no significant differences in the other parameters measured. There was a significant positive correlation between lipoperoxides and reduced glutathione in these children. Conclusion: It is the first time that an increase of lipoperoxidation products has been reported in pubertal boys and this biomarker could play a role in the development of oxidative stress in this stage of life (AU)

[Changes in oxidative stress biomarkers induced by puberty]. / Cambios en biomarcadores del estrés oxidativo inducidos por la pubertad.

AIM: Evaluate the influence of puberty in oxidative stress. SUBJECTS AND METHODS: The study included 38 prepubescent males with Tanner G(1)-P(1) and 32 healthy pubescent boys with Tanner G(3-4)-P(3-4). Weight, height and body mass index, heart rate, blood pressure values were within the 50 percentile 50+/-1SD for their age. The biomarkers were measured in saliva, as a good correlation between saliva and plasma levels has been reported in lipoperoxidation products, reduced glutathione and catalase. RESULTS: Pubescent boys had significantly higher levels of lipoperoxidation products (P<0.001) compared with the prepubertal group, with no significant differences in the other parameters measured. There was a significant positive correlation between lipoperoxides and reduced glutathione in these children. CONCLUSION: It is the first time that an increase of lipoperoxidation products has been reported in pubertal boys and this biomarker could play a role in the development of oxidative stress in this stage of life.

Effects of magnetic stimulation on oxidative stress and skeletal muscle regeneration induced by mepivacaine in rat.

We investigated the effect of magnetic field stimulation (MS) on oxidative damage and skeletal muscle injury prompted by mepivacaine injection in the anterior tibial muscle of Wistar rats. The effects of mepivacaine and MS on oxidative stress were evaluated by lipid peroxidation, GSH levels and catalase activity. Muscle regeneration was analyzed by haematoxylin-eosin stained, NADH-TR histochemical reaction, desmin immunostaining as well as by morphometric parameters such as fibers density and fiber area were evaluated. Our data revealed that mepivacaine induced oxidative stress, that MS prevents the harmful effects induced by mepivacaine and that it facilitates the regeneration process of skeletal muscle. In conclusion, the results show the ability of MS to modify skeletal muscle response to mepivacaine.

Neuroprotective effect of carvedilol and melatonin on 3-nitropropionic acid-induced neurotoxicity in neuroblastoma.

In neurodegenerative diseases, progressive oxidative stress is a major event that precedes neuronal death. Oxidative stress is characterized by an imbalance between oxidants and antioxidants. This imbalance induced oxidative molecular and cell damage, reducing cellular viability. 3-Nitropropionic acid (3NP) causes oxidative stress and other molecular and cellular changes similar to those observed in neurons of patients with Huntington's disease. Since carvedilol and melatonin act as free-radical scavengers, this study examined the effect of carvedilol (10(-5) M) and melatonin (10(-5) M) on oxidative and cell damage induced by 3NP in N1E-115 neuroblastoma cells. Carvedilol and melatonin prevented the increases in lipid peroxidation and total LDH activity, as well as the depletion of reduced glutathione (GSH) and the reduction of antioxidative enzymes activities in N1E-115 cells incubated with 100 mM 3NP. All these carvedilol and melatonin effects were more intense when the drugs were added before rather than after inducing the damage by 3NP. These results also provided evidence supporting the hypothesis that carvedilol and melatonin can be useful for treating neurodegenerative diseases, such as Huntington's disease.

Fat overload aggravates oxidative stress in patients with the metabolic syndrome.

BACKGROUND: Patients with the metabolic syndrome have greater levels of oxidative stress. However, as the response of markers of this stress to a fat overload is unknown, we evaluated certain markers of oxidative stress in these patients. MATERIAL AND METHODS: The study population comprised 93 subjects (70 men and 23 women): 13 healthy people (controls) with a mean age of 48.81 +/- 9.01 years and 80 patients with the metabolic syndrome (mean age, 43.25 +/- 11.55 years), according to the Adult Treatment Panel III criteria. All the participants were given a 60 g fat overload (Supracal). Three hours later the following biomarkers of oxidative stress were measured: lipid peroxidation products, protein carbonyl groups, reduced glutathione, glutathione peroxidase (GSH-Px), catalase, superoxide dismutase, glutathione reductase (GSH-Road) and glutathione S-transferase. The levels of oxidized glutathione (GSSG) were calculated. RESULTS: Compared with the controls, the patients showed greater baseline oxidative stress, higher levels of lipid peroxidation products and oxidized glutathione, and lower levels of reduced glutathione, glutathione peroxidase activity, glutathione reductase and glutathione transferase. This stress was more intense after the subjects received a fat overload, more so in the patients who experienced a greater reduction in GSHpx and GSHrd antioxidant activity and a greater increase in the levels of carbonylated proteins and lipoperoxides than the controls. CONCLUSIONS: Patients with the metabolic syndrome have greater oxidative stress than healthy people. The variation in markers of this stress after a fat overload was even more pronounced in the patients.

Similar increase in oxidative stress after fat overload in persons with baseline hypertriglyceridemia with or without the metabolic syndrome.

OBJECTIVE: We compared the levels of biomarkers of oxidative stress before and after a fat overload in three groups. MATERIALS AND METHODS: 17 controls and two groups with hypertriglyceridemia: 43 without the metabolic syndrome (TG-non-MS) and 29 with the metabolic syndrome (TG-MS). All subjects underwent a 60 g fat overload. Baseline measurements included glucose, BMI (body mass index), waist circumference and HOMA IR (homeostasis model assessment insulin resistance). Cholesterol, triglycerides, HDL (high density lipoprotein) cholesterol, TNF-alpha (tumor necrosis factor) and IL-6 (interleukin-6), lipoperoxide (LPO), carbonylated proteins, reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GSH-PX), glutathione reductase (GSH-Rd), catalase and glutathione transferase (GST) were measured at baseline and 3 h after fat overload. RESULTS: Compared to the controls, the two patient groups had higher plasma levels at baseline and after overload of cholesterol, triglycerides and apolipoprotein B, LPO, carbonylated proteins and GSSG, and lower levels of antioxidants at baseline and after the fat overload. CONCLUSION: The two patient groups had the same degree of oxidative stress.

Grafts of extra-adrenal chromaffin cells as aggregates show better survival rate and regenerative effects on parkinsonian rats than dispersed cell grafts.

The objective was to discern the neuroregenerative effect of grafts of extra-adrenal cells of the Zuckerkandl's paraganglion (ZP) in the nigrostriatal circuit, by using the retrograde model of parkinsonism in rats. The antiparkinsonian efficacy of two types of grafting procedures was studied (cell aggregates vs. dispersed cells), and GDNF and TGFbeta(1) (dopaminotrophic factors) as well as dopamine presence in extra-adrenal tissue was analyzed. Extra-adrenal chromaffin cells are noradrenergics, tissue dopamine is low, and they express both GDNF and TGFbeta(1). Grafts of cell aggregates, not of dispersed cells, exerted a trophic regeneration of the host striatum, leading to amelioration of motor deficits. Sprouting of spared dopaminergic fibers within the striatum, reduction of dopamine axon degeneration, and/or enhanced phenotypic expression of TH would explain striatal regeneration. Grafted cells as aggregates showed a better survival rate than dispersed cells, and they express higher levels of GDNF. Higher survivability and GDNF content together with the neurorestorative and dopaminotrophic action of both GDNF and TGFbeta(1) could account for striatal recovery and functional amelioration after grafting ZP cell aggregates. Finally, nigral degeneration and partial degeneration of ventral tegmental area were not precluded after transplantation, indicating that the trophic effect of grafts was local within the host striatum.