RESUMEN
Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder. More than 95% of classic RETT syndrome cases result from pathogenic variants in the methyl-CpG binding protein 2 (MECP2) gene. Nevertheless, it has been established that a spectrum of neuropsychiatric phenotypes is associated with MECP2 variants in both females and males. We previously reported that microtubule growth velocity and vesicle transport directionality are altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared to that of their wild-type littermates suggesting deficit in microtubule dynamics. In this study, we report that administration of tubastatin A, a selective HDAC6 inhibitor, restored microtubule dynamics in Mecp2-deficient astrocytes. We furthermore report that daily doses of tubastatin A reversed early impaired exploratory behavior in male Mecp2308/y mice. These findings are a first step toward the validation of a novel treatment for RTT.
Asunto(s)
Conducta Animal , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/uso terapéutico , Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/psicología , Animales , Astrocitos/metabolismo , Conducta Exploratoria , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microtúbulos/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Conducta SocialRESUMEN
BACKGROUND/AIM: Recognition of the limitations of liver biopsies has led to the need for non-invasive tests to assess liver fibrosis from intensity and kinetic point of views. The aim of the present study was to evaluate non-invasive ultrasonic tissue characterization for the continuous monitoring of this process in mice. METHODS: Twelve-week-old male and female C57Bl6/J mice were submitted to repetitive carbon-tetrachloride (CCl4) intraperitoneal injections during 8 weeks or analysed 28 days after common bile duct ligation (BDL). The extent and kinetic of the disease progression were followed by the measurement of ultrasound backscatter intensity. This was compared with histological and blood parameter analysis. RESULTS: CCl4 induced a progressive increase in in vivo liver tissue backscatter intensity in both males and females. This increase was mainly correlated with interstitial fibrosis and, to a lower extent, with nuclear surface of the hepatocytes. A similar result was found after BDL. CONCLUSIONS: These data demonstrate for the first time in a systematic study that ultrasound tissue characterization can be used as a reliable tool to follow liver remodelling in mice continuously.