Enhanced markers of oxidative stress, altered antioxidants and NADPH‐oxidase activation in brains from Fragile X mental retardation 1‐deficient mice, a pathological model for Fragile X syndrome

Abstract

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.

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

“…One important outcome of this model is the identification of physiological pathways contributing to the pathogenesis. We have already described in a previous work the implication of oxidative stress as a primary factor involved in Fmr1-KO brain pathophysiology (el Bekay et al, 2007). The experimental procedure is now supported by the correction of deleterious effects of oxidative stress with a-tocopherol chronic treatment.…”

“…Positive effects of a-tocopherol on the Fmr1-knockout mouse Y de Diego-Otero et al homeostasis in Fmr1-KO mice (Brown et al, 2001;Miyashiro et al, 2003;Gruss and Braun, 2004), together with our previous results demonstrating that NADPHoxidase activation as a major source of extracellular oxygenfree radical production in the brain of the fragile X mouse model (El Bekay et al, 2007), prompted us to study the existence of oxidative stress. As phenotypic alterations of fragile X patients and Fmr1-KO mice are based on multiple molecular alterations, the existence of an abnormal substrate in redox homeostasis might be a common The Fmr1-KO group showed an enhanced hyperactivity in both novelty (NOV) and familiarity (FAM) environments and also an absence of habituation of the vehicle Fmr1-KO group in comparison to the vehicle WT-control group.…”

“…The molecular basis of oxidative stress contribution to the Fmr1-KO mouse phenotype was previously analyzed, showing that NADPH-oxidase activation can be a major source of extracellular oxygen-free radical production in the brain (El Bekay et al, 2007). Neurons are highly vulnerable to the oxidant threat because of its high rate of aerobic metabolism and the elevated concentration of oxidizable molecules.…”

“…Inadequate regulation of stress responses and oxidative stress are implicated in the pathogenesis of systemic and neurodegenerative diseases, and can be observed in Down's syndrome and autism (Iannello et al, 1999;Chauhan and Chauhan, 2006). Our previous studies have linked the increased generation of reactive oxygen species (ROS), NADPH-oxidase activation, and the moderate increase of brain oxidative stress, as key pathological components in the mouse model of fragile X syndrome (el Bekay et al, 2007).…”

Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

“…Individuals with autistic FXS have reported a higher level of oxidative stress. There is an increased response of reactive oxygen species (ROS) that is the cause of FMRP deficiency [30]. In the Fmr1 knockout (KO) mice model, a validated model for the FXS, the antioxidant system is deficient [31] and that lead to the pathophysiology of FXS.…”