Impact of Repetitive Transcranial Magnetic Stimulation on Neurocognition and Oxidative Stress in Relapsing-Remitting Multiple Sclerosis: A Case Report.

Multiple sclerosis (MS) is a neurodegenerative condition whose manifestation and clinical evolution can present themselves in very different ways. Analogously, its treatment has to be personalized and the patient's response may be idiosyncratic. At this moment there is no cure for it, in addition to its clinical course sometimes being torpid, with a poor response to any treatment. However, Transcranial Magnetic Stimulation (TMS) has demonstrated its usefulness as a non-invasive therapeutic tool for the treatment of some psychiatric and neurodegenerative diseases. Some studies show that the application of rTMS implies improvement in patients with MS at various levels, but the effects at the psychometric level and the redox profile in blood have never been studied before, despite the fact that both aspects have been related to the severity of MS and its evolution. Here we present the case of a woman diagnosed with relapsing-remitting multiple sclerosis (RRMS) at the age of 33, with a rapid progression of her illness and a poor response to different treatments previously prescribed for 9 years. In view of the patient's clinical course, a compassionate treatment with rTMS for 1 year was proposed. Starting from the fourth month of treatment, when reviewing the status of her disease, the patient denoted a clear improvement at different levels. There followed out psychometric evaluations and blood analyses, that showed both an improvement in her neuropsychological functions and a reduction in oxidative stress in plasma, in correspondence with therTMS treatment.

Clinical and Neurochemical Effects of Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis: A Study Protocol for a Randomized Clinical Trial.

Background: Transcranial Magnetic Stimulation (TMS) is a technique based on the principles of electromagnetic induction. It applies pulses of magnetic radiation that penetrate the brain tissue, and it is a non-invasive, painless, and practically innocuous procedure. Previous studies advocate the therapeutic capacity of TMS in several neurodegenerative and psychiatric processes, both in animal models and in human studies. Its uses in Parkinson's disease, Alzheimer's disease and in Huntington's chorea have shown improvement in the symptomatology and in the molecular profile, and even in the cellular density of the brain. Consequently, the extrapolation of these TMS results in the aforementioned neurodegenerative disease to other entities with etiopathogenic and clinical analogy would raise the relevance and feasibility of its use in multiple sclerosis (MS). The overall objective will be to demonstrate the effectiveness of the TMS in terms of safety and clinical improvement, as well as to observe the molecular changes in relation to the treatment. Methods and Design: Phase II clinical trial, unicentric, controlled, randomized, single blind. A total of 90 patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) who meet all the inclusion criteria and do not present any of the exclusion criteria that are established and from which clinically evaluable results can be obtained. The patients included will be assigned under the 1:1:1 randomization formula, constituting three groups for the present study: 30 patients treated with natalizumab + white (placebo) + 30 patients treated with natalizumab + TMS (1 Hz) + 30 patients treated with natalizumab + TMS (5 Hz). Discussion: Results of this study will inform on the efficiency of the TMS for the treatment of MS. The expected results are that TMS is a useful therapeutic resource to improve clinical status (main parameters) and neurochemical profile (surrogate parameters); both types of parameters will be checked. Ethics and Dissemination: The study is approved by the Local Ethics Committee and registered in https://clinicaltrials.gov (NCT04062331). Dissemination will include submission to a peer-reviewed journal, patients, associations of sick people and family members, healthcare magazines and congress presentations. Trial Registration: ClinicalTrials.gov ID: NCT04062331 (registration date: 19th/ August/2019). Version Identifier: EMTr-EMRR, ver-3, 21/11/2017.

Extra-Virgin Olive Oil Modifies the Changes Induced in Non-Nervous Organs and Tissues by Experimental Autoimmune Encephalomyelitis Models.

This study reveals the existence of oxidative stress (reactive oxygen species (ROS)) in non-nervous organs and tissues in multiple sclerosis (MS) by means of a model of experimental autoimmune encephalomyelitis (EAE) in rats. This model reproduces a similar situation to MS, as well as its relationship with intestinal microbiota starting from the changes in bacterial lipopolysaccharide levels (LPS) in the outer wall of the gram-negative bacteria. Finally, the administration of extra-virgin olive oil (EVOO), hydroxytirosol (HT), and oleic acid (OA) exert beneficial effects. Twenty-five Dark Agouti two-month-old male rats, weighing around 190 g, were distributed into the following groups: Control, EAE (experimental autoimmune encephalomyelitis group), EAE + EVOO, EAE + HT, and EAE + OA. The glutathione redox system with the EAE was measured in heart, kidney, liver, and small and large intestines. The LPS and the correlation with oxidative stress in the small and large intestines were also investigated. The results showed that (1) the oxidative damage in the EAE model affects non-nervous organs and tissues; (2) The LPS is related to inflammatory phenomena and oxidative stress in the intestinal tissue and in other organs; (3) The administration of EVOO, HT, and OA reduces the LPS levels at the same time as minimizing the oxidative damage; (4) EVOO, HT, and OA improve the disease's clinical score; and (5) on balance, EVOO offers a better neuroprotective effect.

Comparative of transcranial magnetic stimulation and other treatments in experimental autoimmune encephalomyelitis.

The effects of transcranial magnetic stimulation (TMS), natalizumab (nata), dimethyl fumarate (DMF) and dexamethasone (DEX) on clinical score and oxidative stress produced by a single dose of myelin oligodendrocyte glycoprotein (MOG) in tail of Dark Agouti rats was studied. TMS (60Hz and 0.7 mT), nata (5mg/kg), DMF (15mg/kg) and DEX (300µg/kg) was applied for 21 after the administration of MOG (150µg). We estimated clinical score, as well as lipid peroxides, carbonylated proteins and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio content in brain, spinal cord and blood. MOG triggered significant increase in clinical score and in the levels of lipid peroxides and carbonylated proteins levels, but reduced GSH/GSSG ratio in brain, spinal cord and blood. Both TMS and clinical treatments, although TMS more significantly, decreased the changes caused by MOG administration. These results support the antioxidant and neuroprotective action of TMS, as well as an activity higher than other clinical treatments.

Effects of transcranial magnetic stimulation on oxidative stress in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) reproduces a multiple sclerosis (MS)-like experimental model. The main objective was to evaluate the effect of extremely low-frequency electromagnetic fields (EL-EMF) application, like a paradigm of transcranial magnetic stimulation (TMS) in the development of EAE. Rats were injected with a single dose of 150 µg of myelin oligodendrocyte glycoprotein (MOG, fragment 35-55) to produce experimental MS. To assess the effect of TMS application in EAE, the rats were treated with TMS (60 Hz and 0.7 mT) for 2 h in the morning, once a day, 5 days a week, during 3 weeks. TMS was applied to the head. The effect of TMS on EAE was evaluated as motor symptoms and, oxidative and cell damage. The data showed that MOG induced motor symptoms as tail paralysis and limb paresis/paralysis, oxidative stress and cell death similar to MS when compared with control animals. Importantly, TMS application attenuated motor symptoms, oxidative and cell damage, whereas it increased antioxidant system. Our findings suggest that: (i) MOG reproduces an experimental model of MS characterised by oxidative and cell damage; and (ii) TMS application decreases oxidative stress and cell death induced by MOG.

Lipopolysaccharide Binding Protein and Oxidative Stress in a Multiple Sclerosis Model.

Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that altering certain bacterial populations present in the gut may lead to a proinflammatory condition, that could result in the development of multiple sclerosis (MS). Also, Reactive Oxygen Species seem to be involved in the course of MS. In this study, it has been aimed to relate all these variables starting from an analysis of the lipopolysaccharide (LPS) and LPS-binding protein (LBP) with the determination of parameters related to oxidative stress in the blood, brain and spinal cord. For this purpose, samples obtained from EAE rats and relapsing-remitting (RRMS) MS patients were used. In addition, EAE rats were treated with Natalizumab, N-acetyl-cysteine and dimethyl fumarate. Natalizumab was also employed in RRMS. The results of this study revealed an improvement in the clinical symptoms of the EAE and MS with the treatments, as well as a reduction in the oxidative stress parameters and in LBP. Correlations between the clinical variables of the disease, i.e. oxidative damage and LBP, were established. Although the conclusions of this research are indeed relevant, further investigation would be necessary to establish the intrinsic mechanisms of the MS-oxidative stress-microbiota relationship.

Transcranial magnetic stimulation modifies astrocytosis, cell density and lipopolysaccharide levels in experimental autoimmune encephalomyelitis.

AIMS: Experimental autoimmune encephalomyelitis (EAE) is considered a valid experimental model for multiple sclerosis, a chronic neuroinflammatory condition of the central nervous system. Additionally, some evidence has shown that some microbial products such as the bacterial lipopolysaccharide could lead to the activation of reactive immune cells, triggering neuroinflammation. Several studies have found that transcranial magnetic stimulation (TMS) may exert a neuroprotective effect. Therefore, we aimed to assess the effect of TMS on the neuroinflammation occurring in EAE. MATERIALS AND METHODS: A total of 44 male Dark Agouti rats were used. EAE induction was performed administering subcutaneously at the dorsal base of the tail a single dose of myelin oligodendrocyte glycoprotein. Clinical evaluation of motor symptoms was performed. Brain and spinal cord were collected and analyzed for nitric oxide, bacterial lipopolysaccharide and lipopolysaccharide-binding protein. We also carried out a histologic exam, which included an astrocyte immunostaining and Nissl staining for the assessment of brain cell density and pyknotic nuclei. KEY FINDINGS: TMS effectively ameliorated motor impairment secondary to EAE. This form of magnetic field was capable of decreasing the proliferation of astrocytes as a response to the autoimmune attack, reducing the content of nitric oxide, bacterial lipopolysaccharide and lipopolysaccharide-binding protein in central nervous system. Moreover, in treated animals, brain cell density was improved and the number of pyknotic nuclei was decreased. SIGNIFICANCE: Transcranial magnetic stimulation modifies astrocytosis, cell density and lipopolysaccharide levels in EAE. These results suggest that TMS could be a promising treatment for neuroinflammatory conditions such as multiple sclerosis.

Elevated melatonin levels in natalizumab-treated female patients with relapsing-remitting multiple sclerosis: relationship to oxidative stress.

Natalizumab is currently the most successful clinical treatment for multiple sclerosis. The use of this drug is associated with the reduction in the number of relapses and a slowing in disease progression, as well as an improvement in signs and symptoms displayed by the patients. To evaluate the effect of natalizumab on melatonin and its relationship with peripheral oxidative damage, we studied the serum melatonin levels in 18 patients with relapsing-remitting multiple sclerosis. Natalizumab caused significant increases in serum melatonin concentrations. This change was associated with a rise in increase of antioxidants and a reduction in oxidative stress biomarkers. In conclusion, these data may explain, at least in part, some of the beneficial effects exhibited by disease antibody such as its antioxidant capacity.

Oxidative stress and inflammation biomarkers in the blood of patients with Huntington's disease.

OBJECTIVES: Huntington's disease (HD) is a neurodegenerative disorder for which there is no effective treatment. Oxidative stress and inflammation are known to be involved in HD, but the precise relationship between the two remains unclear. The aim of this study was to analyze oxidative stress and inflammation biomarkers in blood of patients with HD with a view to identifying potential links between them. METHODS: Blood samples were collected from 13 patients with HD and from 10 age- and sex-matched controls, and the following were measured: C-reactive proteins, myeloperoxidase (MPO)/white blood cell (WBC) ratio, interleukin-6 (IL-6), thioredoxin reductase-1 (TrRd-1), thioredoxin-1 (Trx-1), total nitrites (NOx), nitric oxide synthase (NOS) and nitrotyrosine. RESULTS: Results showed that HD is associated to a reduction of TrRd-1 and Trx-1 levels in plasma and erythrocytes, and with an increase in the MPO/WBC ratio. A positive correlation was observed between global oxidative stress (GOS) and MPO/WBC. No changes were found in NOS and Nox levels with respect to controls. CONCLUSION: Oxidative damage may be linked to the inflammatory response in HD, via a peripheral immune response.

Peripheral oxidative stress in relapsing-remitting multiple sclerosis.

OBJECTIVES: To evaluate levels of oxidative stress in blood samples in patients with relapsing-remitting MS (RR-MS). DESIGN AND METHODS: Peripheral blood samples were collected from 24 RR-MS patients and 15 healthy controls. Levels of the following were measured: carbonylated proteins, 8-hydroxy-2'deoxyguanosine (8OHdG), total glutathione, reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratio, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRd), glutathione-S-transferase (GST), myeloperoxidase (MPO), antioxidant gap, total antioxidant capacity (PAO), global oxidative stress (GOS), serum vascular cell adhesion molecule-1 (sVCAM-1) and serum inter-cellular adhesion molecule 1 (sICAM-1). RESULTS: Values for carbonylated proteins, 8OHdG, total glutathione, GSH, GSH/GSSG ratio, SOD, GRd and GOS were significantly higher in RR-MS patients than in healthy controls. By contrast, PAO, GSSG, GPx and GST were lower in RR-MS patients. CONCLUSION: Oxidative stress plays a major role in MS, and is observed prior to relapse.

Biomarcadores de estrés oxidativo como indicadores de actividad en la enfermedad articular inflamatoria crónica / Oxidative stress biomarkers as indicator of chronic inflammatory joint diseases stage

Objetivo Evaluar la participación del estrés oxidativo (EO) en la enfermedad articular inflamatoria crónica (EAIC), así como su posible uso como biomarcador diagnóstico. Pacientes y métodos Se estudiaron 29 pacientes con EAIC: 18 con artritis reumatoide (AR): 13 activos/5 inactivos; y 11 con espondilitis anquilosante (EA): 7 activos/4 inactivos, y como grupo control, 13 sujetos sanos. Los pacientes fueron clasificados según los siguientes criterios de actividad: escala de actividad de la enfermedad (DAS-28) para AR, e índice de actividad de enfermedad (BASDAI) y la escala visual analógica (EVA) de dolor nocturno para EA. Las concentraciones plasmáticas de los biomarcadores de estrés oxidativo fueron cuantificadas mediante técnicas espectrofotométricas y el análisis estadístico realizado, mediante el programa estadístico SPSS. Resultados Los pacientes con EAIC activa presentan un intenso EO, caracterizado por elevación de los parámetros indicadores de daño oxidativo y disminución de los sistemas antioxidantes, junto con una mayor cantidad de mieloperoxidasa. En los pacientes con EAIC inactiva sólo encontramos cambios en los niveles de glutatión oxidado (GSSG) y en el cociente glutatión reducido (GSH)/GSSG, y no en los indicadores de daño oxidativo ni en los sistemas antioxidantes. Conclusiones Nuestros datos indican que: a) los pacientes con EAIC activa presentan un intenso EO; b) la EAIC inactiva cursa con producción de especies reactivas sin llegar a desencadenar daño oxidativo y manteniendo la homeostasis reducción-oxidación, y c) los biomarcadores de EO podrían ser utilizados como indicadores del estado de actividad-inactividad de la EAIC (AU)

Objective To evaluate the participation of oxidative stress (OS) on chronic inflammatory joint disease (CIJD), as well as its possible use as a diagnostic biomarker. Patients and methods The study population comprised 29 patients with CIJD: 18 with rheumatoid arthritis (RA: 13 active/5 inactive); 11 with ankylosing spondylitis (AS: 7 active/4 inactive) and 13 healthy subjects. Activity of the disease was assessed by: RA patients, Disease Activity Score (DAS 28) and AS patients by means of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Oxidative stress biomarkers were determined in plasma using spectrophotometrical techniques. The statistical analysis was carried out using the SSPS statistical package. Results Active CIJD showed a high oxidative stress characterized by increases in oxidative damage markers and a reduction in antioxidative systems, together with a higher myeloperoxidase (MPO) concentration. Inactive CIJD only showed changes in oxidized glutathione (GSSG) and reduced glutathione (GSH)/GSSG ratio levels, without changes in oxidative damage parameters or in antioxidative systems. Conclusions Our data revealed that: i) CIJD presents with a high oxidative stress; ii) inactive CIJD shows a production of reactive species without triggering oxidative damage and maintaining red-ox homeostasis, and iii) the combination of oxidative stress biomarkers may be used as markers of active-inactive stages of CIJD (AU)

[Oxidative stress biomarkers as indicator of chronic inflammatory joint diseases stage]. / Biomarcadores de estrés oxidativo como indicadores de actividad en la enfermedad articular inflamatoria crónica.

OBJECTIVE: To evaluate the participation of oxidative stress (OS) on chronic inflammatory joint disease (CIJD), as well as its possible use as a diagnostic biomarker. PATIENTS AND METHODS: The study population comprised 29 patients with CIJD: 18 with rheumatoid arthritis (RA: 13 active/5 inactive); 11 with ankylosing spondylitis (AS: 7 active/4 inactive) and 13 healthy subjects. Activity of the disease was assessed by: RA patients, Disease Activity Score (DAS 28) and AS patients by means of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Oxidative stress biomarkers were determined in plasma using spectrophotometrical techniques. The statistical analysis was carried out using the SSPS statistical package. RESULTS: Active CIJD showed a high oxidative stress characterized by increases in oxidative damage markers and a reduction in antioxidative systems, together with a higher myeloperoxidase (MPO) concentration. Inactive CIJD only showed changes in oxidized glutathione (GSSG) and reduced glutathione (GSH)/GSSG ratio levels, without changes in oxidative damage parameters or in antioxidative systems. CONCLUSIONS: Our data revealed that: i) CIJD presents with a high oxidative stress; ii) inactive CIJD shows a production of reactive species without triggering oxidative damage and maintaining red-ox homeostasis, and iii) the combination of oxidative stress biomarkers may be used as markers of active-inactive stages of CIJD.

Infliximab reduces myeloperoxidase concentration in chronic inflammatory joint diseases.

UNLABELLED: The present study evaluated the effect of infliximab on the myeloperoxidase (MPO) concentration in chronic inflammatory joint disease. Eighteen patients were divided into active and inactive groups. Erythrocyte sedimentation rate, C-reactive protein, white blood cell counts, MPO concentration, and biomarkers of oxidative stress were measured before and after the infusion of infliximab. Patients with active disease showed increases in concentrations of MPO and biomarkers of oxidation, but decreases in antioxidant parameters. After infliximab treatment, both inflammatory parameters and MPO concentrations were normalized. IN CONCLUSION: (1) the MPO concentration is related to inflammatory activity and could play an important role in the maintenance and outbreak of oxidative stress present in these diseases, and (2) infliximab inhibits MPO concentration.

Effect of 17beta-estradiol on olfactory bulbectomy-induced oxidative stress and behavioral changes in rats.

The present study evaluated 17beta-estradiol (17betaE(2)) (2.5 mg/kg sc) effects on bilateral OBX-induced behavioral changes and oxidative stress. OBX in male Wistar rats produced an increase in lipid peroxidation products and a decline in reduced glutathione (GSH) content and glutathione peroxidase (GSH-Px) activity, together with an increase in caspase-3 activity. Additionally, OBX triggered changes of behavior such as an enhancement of immobility time in the forced swim test and hyperactivity in the open field test. These changes were reversed by treatment with 17betaE(2) (14 days). Our results reveled that 17betaE(2) has a protective effect against oxidative stress, cell damage and behavioral changes induced by OBX, and present antidepressant and antianxiety properties.

Effect of testosterone on oxidative stress and cell damage induced by 3-nitropropionic acid in striatum of ovariectomized rats.

This paper evaluates the effects of testosterone (0.5 mg/kg subcutaneously (s.c.) for 8 days) on oxidative stress and cell damage induced by 3-nitropropionic acid (20 mg/kg intraperitoneally (i.p.) for 4 days) in ovariectomized rats. Gonadectomy triggered oxidative damage and cell loss, evaluated by the detection of caspase-3, whereas 3-nitropropionic acid increased the levels of oxidative stress induced by ovariectomy and prompted cell damage characterized by enhanced levels of lactate dehydrogenase. These changes were blocked by testosterone administration. Our results support the following conclusions: i) ovariectomy triggers oxidative and cell damage via caspase-3 in the striatum; ii) 3-nitropropionic acid exacerbates oxidative stress induced by ovariectomy and leads to cell damage characterized by increased levels of lactate dehydrogenase; iii) testosterone administration decreases oxidative stress and cell damage. Additionally, these data support the hypothesis that testosterone might play an important role in the onset and development of neurodegenerative diseases.

Comparison of melatonin, vitamin E and L-carnitine in the treatment of neuro- and hepatotoxicity induced by thioacetamide.

This study was designed to evaluate and compare the effect of melatonin, vitamin E and L-carnitine on brain and liver oxidative stress and liver damage. Oxidative stress and hepatic failure were produced by a single dose of thioacetamide (TAA) (150 mg kg(-1)) in Wistar rats. A dose of either melatonin (3 mg kg(-1)) vitamin E (20 mg kg(-1) ) or L-carnitine (100 mg kg(-1)) was used. Blood samples were taken from the neck vasculature in order to determine ammonium, blood urea nitrogen (BUN) and liver enzymes. Lipid peroxidation products, glutathione (GSH) content and antioxidative enzymes were determined in cerebral and hepatic homogenates. The results showed a decrease in BUN and in the antioxidant enzymes activities and GSH in the brain and liver. Likewise, TAA induced significant enhancement of lipid peroxidation products levels in both liver and brain, as well as in ammonia values. Melatonin, vitamin E and L-carnitine, although melatonin more significantly, decreased the intensity of the changes produced by the administration of TAA alone. Furthermore melatonin combined with TAA, decreased the ammonia levels and increased the BUN values compared with TAA animals. Also it was more effective than vitamin E or L-carnitine in these actions. These data show the protective effect of these agents, especially melatonin, against oxidative stress and hepatic damage present in fulminant hepatic failure.

Protective effect of carvedilol on oxidative stress induced by okadaic acid in N1E-115 cells.

The effect of carvedilol on oxidative and cell damage induced by okadaic acid in N1E-115 cells were studied. The effects of okadaic acid were evaluated as changes in: the quantity of lipid peroxidation products, protein carbonyl groups, reduced glutathione content (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase and total lactate dehydrogenase (cell LDH). Additionally, a dose of carvedilol (10(-5)M) was added 2h before incubation with okadaic acid (50 nM) and was present until the end of the experiment (2h later added okadaic acid). Our results reveal that okadaic acid induces oxidative stress and an increase of cell LDH in N1E-115 cells, whereas carvedilol prevented the changes prompted by okadaic acid. In conclusion, the data show the protective effect of carvedilol, as well as its ability to modify cell response to okadaic acid, involving like cytoprotective mechanism its antioxidative properties.

17 beta-Estradiol may affect vulnerability of striatum in a 3-nitropropionic acid-induced experimental model of Huntington's disease in ovariectomized rats.

The aim of present study was to clarify the role of female sex hormones in the development and course of neurodegenerative disease in an experimental model of Huntington's disease induced by 3-nitropropionic acid (NPA) (30 mg/kg intraperitoneally (i.p.)/day for 4 days) in ovariectomized rat. Gonadectomy prompted oxidative stress and cell death evaluated by the detection of caspase-3, whereas 3-nitropropionic acid enhanced the oxidative stress induced by ovariectomy and it triggered cell damage characterized by increases of LDH levels. These changes were prevented by administration of 17 beta-estradiol. Our findings suggested that: (i) ovariectomy induced oxidative stress and apoptosis in the brain; (ii) 3-nitropropionic acid exacerbated oxidative stress induced by ovariectomy and shifting cell to cell death; and (iii) 17 beta-estradiol administration decreased oxidative stress and cell death induced by ovariectomy and 3-nitropropionic acid. These results revealed that sex ovarian hormones play a important role in onset and development of neurodegenerative diseases, as well as neuroprotective effects of 17 beta-estradiol against the changes induced ovariectomy and ovariectomy plus 3-nitropropionic acid.

Hepato- and neurotoxicity induced by thioacetamide: protective effects of melatonin and dimethylsulfoxide.

The effects of melatonin and dimethylsulfoxide (DMSO) on liver and brain oxidative stress, hepatic failure and blood urea nitrogen (BUN) level changes produced by a single dose of thioacetamide (TAA) in Wistar rats were studies. A dose of either melatonin (3 mg kg(-1)day(-1)) or DMSO (2 g kg(-1)day(-1)) was injected for 3 days before and for 2 days after the administration of TAA (150 mg kg(-1) i.p.). Blood samples were taken from the neck vascular in order to determine ammonium, BUN and liver enzymes. We estimated lipid peroxidation products, reduced glutathione (GSH) content and catalase activity in liver and brain homogenates. TAA caused significant increases in ammonium and in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) enzymes, while it decreased BUN values. TAA also increased lipid peroxidation product levels, but reduced GSH content and catalase activity in the liver and brain. Both melatonin and DMSO, although melatonin more significantly, decreased the intensity of the changes produced by the administration of TAA alone. Furthermore, melatonin alone or combined with TAA increased the BUN levels and decreased the ammonia values compared with control animals. These results support the antioxidative and neuro-/hepato-protective action of melatonin and a lesser action of DMSO. Likewise, these data seem to support the hypothesis of an effect of melatonin on urea synthesis.

Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington's disease.

The effect of melatonin (1 mg/kg BW i.p./day) on the oxidative changes produced by 3-nitropropionic acid (20 mg/kg BW/day for 4 days) in rat striatal and cortical synaptosomes was investigated. The effects of 3-nitropropionic acid were evaluated as changes in the quantity of lipid peroxidation products, protein carbonyl groups and superoxide dismutase and succinate dehydrogenase activities. 3-Nitropropionic acid caused a rise in lipid peroxidation levels and protein carbonyls content whereas it induced a reduction in the activity of succinate dehydrogenase and triggered an enhancement in superoxide dismutase activity. These changes were prevented by previous administration of melatonin. Our results reveal: (i) 3-nitropropionic acid induces a status of oxidative stress in some brain regions of the Wistar rat; (ii) melatonin prevents the deleterious effects induced by the acid. In conclusion, the results show the ability of melatonin to modify the neural response to 3-nitropropionic acid with the protective mechanism likely involving the antioxidative processes of melatonin.