Natalizumab Modifies Catecholamines Levels Present in Patients with Relapsing- Remitting Multiple Sclerosis.

AIMS: The main aim of this study was to verify the effect of natalizumab on the levels of circulating catecholamines and indolamine and their possible relation with MS. METHODS: For this purpose, 12 healthy individuals (control group) and 12 relapsing-remitting multiple sclerosis patients (RR-MS) were selected. The patients were treated with 300 mg of natalizumab during 56 weeks (1 dose/4 weeks) (MS-56). This selection was based on the McDonalds revision criterion and scheduled to star treatment with natalizumab. Blood samples were taken before treatment (basal level) and after 56 weeks of using natalizumab. Melatonin was measured in serum and in plasma, catecholamines (dopamine, epinephrine, and norepinephrine), carbonylated proteins, 8-hydroxy-2'deoxyguanosine (8OH-dG) and the ratio reduced glutathione/oxidised glutathione (GSH/GSSG). RESULTS: The epinephrine and dopamine levels diminished in the basal group with respect to the control and did not recover normal levels with the treatment. The melatonin was decreased in RR-MS patients and went back to its normal levels with natalizumab. Norepinephrine was increased in RR-MS and decreased in MS-56 until it equalled the control group. CONCLUSION: Natalizumab normalizes altered melatonin and norepinephrine levels in MS.

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.

Effect of natalizumab on oxidative damage biomarkers in relapsing-remitting multiple sclerosis.

BACKGROUND: Natalizumab is a monoclonal antibody used to treat multiple sclerosis. This study sought to determine whether the protective action of natalizumab involved a reduction in oxidative damage. METHODS: Twenty-two multiple sclerosis patients fulfilling the revised McDonald criteria were assigned to treatment with 300 mg natalizumab intravenously once monthly (infusion every 4 weeks) in accordance with Spanish guidelines. Carbonylated proteins, 8-hydroxy-2'-deoxyguanosine, total glutathione, reduced glutathione, superoxide dismutase, glutathione peroxidase, and myeloperoxidase levels were measured at baseline and after 14 months' treatment, and the antioxidant gap was calculated. RESULTS: Natalizumab prompted a drop in oxidative-damage biomarker levels, together with a reduction both in myeloperoxidase levels and in the myeloperoxidase/neutrophil granulocyte ratio. Interestingly, natalizumab induced nuclear translocation of Nrf2 and a fall in serum vascular cell adhesion molecule-1 levels. CONCLUSION: These findings suggest that natalizumab has a beneficial effect on oxidative damage found in MS patients.

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.

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.

Melatonin improves 3-nitropropionic acid induced behavioral alterations and neurotrophic factors levels.

OBJECTIVE: This study sought to determine whether melatonin causes changes in neurotrophic factors and it protects against the mycotoxin 3-nitropropionic acid (3-NP) in brain tissue. METHODS: Rats were given 3-NP over four consecutive days (20 mg/kg BW), while melatonin was administered over 21 days (1 mg/kg/BW), starting after the last injection of 3-NP. RESULTS: Rats treated with 3-NP displayed significant changes in neurotrophic factor (BDNF and GDNF) levels, together with alterations in behavior; they also displayed extensive oxidative stress and a massive neuronal damage. CONCLUSIONS: Melatonin improved behavioral alterations, reduced oxidative damage, lowered neurotrophic factor levels and neuronal loss in 3-NP-treated rats. These results suggest that melatonin exerts a neuroprotective action.

Natalizumab y reducción de los niveles de proteínas carboniladas en pacientes con esclerosis múltiple / Natalizumab and reduction of carbonylated proteins in patients with multiple sclerosis

Introducción. Es conocida la especial sensibilidad del sistema nervioso central al daño oxidativo, así como la relación entre éste y la respuesta inflamatoria. Recientes estudios han mostrado que el estrés oxidativo está presente en la instauración y evolución de la esclerosis múltiple (EM). Uno de los más recientes tratamientos en este proceso es el natalizumab,un anticuerpo monoclonal. Objetivo. Evaluar si el efecto terapéutico del natalizumab se asocia con la gravedad de la enfermedad y el daño oxidativo. Pacientes y métodos. Se reclutó para el estudio a 20 pacientes con EM remitente recurrente (EMRR) incluidos en terapia con natalizumab y distribuidos según la Expanded Disability Status Scale (EDSS) en dos grupos: EMRR-1 (EDSS < 5) yEMRR-2 (EDSS ≥ 5). Se obtuvieron muestras sanguíneas para un estudio del perfil oxidativo.Resultados. Los datos mostraron un descenso en las proteínas carboniladas tras el tratamiento con natalizumab. La reducciónde daño oxidativo valorada como oxidación de proteínas es significativa entre la situación previa del paciente (basal) y tras 14 meses de tratamiento. El decremento más significativo coincidió con los pacientes de mayor gravedad en el proceso. Si bien no ha sido posible establecer una correlación, la significación estadística es mayor para pacientes del grupo EMRR-2 tratados con natalizumab. Por su parte, los sistemas antioxidantes no mostraron cambios estadísticamentesignificativos. Conclusión. El natalizumab induce una reducción en los niveles de proteínas carboniladas (AU)

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 developmentof 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 tatistically significant changes.Conclusions. Natalizumab brings about a reduction in carbonylated protein levels (AU)