Protective effects of melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic research model for the fragile X syndrome.
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.
Romero-Zerbo
Yanina
Y
Research Laboratory, Fundación IMABIS, Hospital Carlos Haya, Málaga, Spain.
Decara
Juan
J
el Bekay
Rajaa
R
Sanchez-Salido
Lourdes
L
Del Arco-Herrera
Ignacio
I
de Fonseca
Fernando Rodríguez
FR
de Diego-Otero
Yolanda
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D051860:Fragile X Messenger Ribonucleoprotein 1; D005978:Glutathione; D008550:Melatonin; D017392:Thiobarbituric Acid Reactive Substances; C497684:Fmr1 protein, mouse