Alpha-tocopherol protects against oxidative stress in the fragile X knockout mouse: an experimental therapeutic approach for the Fmr1 deficiency.
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.
de Diego-Otero
Yolanda
Y
Fundacion IMABIS, Hospital Carlos Haya, Malaga, Spain. yolanda.diego.exts@juntadeandalucia.es
Romero-Zerbo
Yanina
Y
el Bekay
Rajaa
R
Decara
Juan
J
Sanchez
Lourdes
L
Rodriguez-de Fonseca
Fernando
F
del Arco-Herrera
Ignacio
I
D000111:Acetylcysteine / Q000627:therapeutic use; D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D005609:Free Radicals / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010641:Phenotype; D051571:Protein Kinase C-alpha / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology; D024502:alpha-Tocopherol / Q000627:therapeutic use*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D000111:Acetylcysteine; D000975:Antioxidants; D051860:Fragile X Messenger Ribonucleoprotein 1; D005609:Free Radicals; D009479:Neuropeptides; D051571:Protein Kinase C-alpha; D024502:alpha-Tocopherol; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C497684:Fmr1 protein, mouse; C484602:Rac1 protein, mouse