RESUMEN
BACKGROUND: Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN: A phase II randomized, double-blind pilot clinical trial. SCOPE: male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION: clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION: A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).
Asunto(s)
Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Proyectos de Investigación , alfa-Tocoferol/uso terapéutico , Adolescente , Conducta del Adolescente/efectos de los fármacos , Desarrollo del Adolescente/efectos de los fármacos , Antioxidantes/efectos adversos , Ácido Ascórbico/efectos adversos , Biomarcadores/sangre , Lista de Verificación , Niño , Conducta Infantil/efectos de los fármacos , Desarrollo Infantil/efectos de los fármacos , Protocolos Clínicos , Cognición/efectos de los fármacos , Método Doble Ciego , Combinación de Medicamentos , Síndrome del Cromosoma X Frágil/sangre , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/psicología , Humanos , Masculino , Proyectos Piloto , España , Factores de Tiempo , Resultado del Tratamiento , Escalas de Wechsler , alfa-Tocoferol/efectos adversosRESUMEN
Fragile X syndrome is the most common form of inherited mental retardation. It is typically caused by a mutation of the Fragile X mental-retardation 1 (Fmr1) gene. To better understand the role of the Fmr1 gene and its gene product, the fragile X mental-retardation protein in central nervous system functions, an fmr1 knockout mouse that is deficient in the fragile X mental-retardation protein was bred. In the present study, fragile X mental retardation 1-knockout and wild-type mice are used to determine behaviour and oxidative stress alterations, including reduced glutathione, oxidized glutathione and thiobarbituric acid-reactive substances, before and after chronic treatment with melatonin or tianeptine. Reduced glutathione levels were reduced in the brain of fmr1-knockout mice and chronic melatonin treatment normalized the glutathione levels compared with the control group. Lipid peroxidation was elevated in brain and testes of fmr1-knockout mice and chronic melatonin treatment prevents lipid peroxidation in both tissues. Interestingly, chronic treatment with melatonin alleviated the altered parameters in the fmr1-knockout mice, including abnormal context-dependent exploratory and anxiety behaviours and learning abnormalities. Chronic treatment with tianeptine (a serotonin reuptake enhancer) did not normalize the behaviour in fmr1-knockout mice. The prevention of oxidative stress in the fragile X mouse model, by an antioxidant compound such as melatonin, emerges as a new and promising approach for further investigation on treatment trials for the disease.
Asunto(s)
Antioxidantes/farmacología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Melatonina/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Glutatión/metabolismo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Melatonina/uso terapéutico , Ratones , Ratones Noqueados , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Fragile X syndrome is the most common genetic cause of mental disability. The mechanisms underlying the pathogenesis remain unclear and specific treatments are still under development. Previous studies have proposed an abnormal hypothalamic-pituitary-adrenal axis and high cortisol levels are demonstrated in the fragile X patients. Additionally, we have previously described that NADPH-oxidase activation leads to oxidative stress in the brain, representing a pathological mechanism in the fragile X mouse model. Fmr1-knockout mice develop an altered free radical production, abnormal glutathione homeostasis, high lipid and protein oxidation, accompanied by stress-dependent behavioral abnormalities and pathological changes in the first months of postnatal life. Chronic pharmacological treatment with alpha-tocopherol reversed pathophysiological hallmarks including free radical overproduction, oxidative stress, Rac1 and alpha-PKC activation, macroorchidism, and also behavior and learning deficits. The restoration of the oxidative status in the fragile X mouse emerges as a new and promising approach for further therapeutic research in fragile X syndrome.
Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , alfa-Tocoferol/uso terapéutico , Acetilcisteína/uso terapéutico , Envejecimiento , Animales , Antioxidantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Miedo/efectos de los fármacos , Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/psicología , Radicales Libres/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Noqueados , Neuropéptidos/metabolismo , Fenotipo , Proteína Quinasa C-alfa/metabolismo , Estrés Psicológico/fisiopatología , Proteínas de Unión al GTP rac/metabolismo , Proteína de Unión al GTP rac1RESUMEN
Fragile X syndrome is the most common form of inherited mental retardation in humans. It originates from the loss of expression of the Fragile X mental retardation 1 (FMR1) gene, which results in the absence of the Fragile X mental retardation protein. However, the biochemical mechanisms involved in the pathological phenotype are mostly unknown. The availability of the FMR1-knockout mouse model offers an excellent model system in which to study the biochemical alterations related to brain abnormalities in the syndrome. We show for the first time that brains from Fmr1-knockout mice, a validated model for the syndrome, display higher levels of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activation, lipid peroxidation and protein oxidation than brains from wild-type mice. Furthermore, the antioxidant system is deficient in Fmr1-knockout mice, as shown by altered levels of components of the glutathione system. FMR1-knockout mice lacking Fragile X mental retardation protein were compared with congenic FVB129 wild-type controls. Our results support the hypothesis that the lack of Fragile X mental retardation protein function leads to a moderate increase of the oxidative stress status in the brain that may contribute to the pathophysiology of the Fragile X syndrome.