1. ¹Fundacion IMABIS, Hospital Carlos Haya, Malaga, Spain
2. ²CIBER Fisiopatologia Obesidad y Nutricion (CB06/03), Instituto de Salud Carlos III, Spain
3. ³Instituto de Innovación para el Bienestar Ciudadano, Parque Tecnologico de Andalucia, Malaga, Spain

Correspondence: Dr Y de Diego Otero, Fundacion IMABIS, Hospital Carlos Haya, Laboratorio de Investigacion, Hospital Civil, Pabellon 5-Sot, 29011 Malaga, Spain. Tel: +34 951290346; Fax: +34 951290302; E-mail: yolanda.diego.exts@juntadeandalucia.es

Received 18 February 2008; Revised 31 July 2008; Accepted 19 August 2008; Published online 8 October 2008.

Abstract

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 -tocopherol reversed pathophysiological hallmarks including free radical overproduction, oxidative stress, Rac1 and -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.