Inhibition of Histone Deacetylases (HDAC) has beneficial effects in mouse models of muscular dystrophies indicating that HDACs are a potential pharmacological target for Duchenne Muscular Dystrophy (DMD). We have studied the effects of Givinostat, a potent HDAC inhibitor, on histological and functional parameters in mdx mice. Givinostat 1, 5 and 10 mg/kg ip was administered daily for 90 days to mdx mice that were 2 month old at the beginning of the treatment. Saline (SAL) and Trichostatin 0.6 mg/kg po (TSA) were administered as controls. Eight animals per group were treated. Motor function performance (treadmill) and body weight were measured at different time points. At the end of treatment quadriceps, tibialis anteriore and blood were collected for weight assessment, histological processing and pharmacokinetic measurements. Fibrosis (Masson's trichrome staining), inflammatory infiltration (Myeloperoxidase) and muscle cross sectional area (H&E staining) were measured on specimens of tibialis anteriore. Results were subjected to statistical analysis and pk-pd analysis. P values are versus SAL. A treatment effect was observed on body weight. Quadriceps weights were increased by Givinostat 5 and 10 mg/kg and TSA (p < 0.05). Givinostat dose dependently reduced fibrosis (p < 0.001 all doses), and inflammation (p < 0.05, 5 and 10 mg/kg). A trend shift towards larger diameter muscle fibres was observed with Givinostat 10 mg/kg. Givinostat 5 mg/kg improved treadmill preformance (p < 0.05 at 60 days). TSA increased quadriceps weight (p < 0.01) and reduced fibrosis (p < 0.001). The pk-pd analysis confirmed the relationship between Givinostat exposures and histological and functional effects and indicated that blood exposures of nearly 600 h nmol/L are needed to obtain the desired effects. This study in mdx mice shows a clear dose and/or concentration dependent effect on functional and histological parameters and supports the clinical development of Givinostat for the treatment of DMD.
Givinostat improves histological and functional parameters in mdx mice dose and concentration dependently
Mozzetta C;
2012
Abstract
Inhibition of Histone Deacetylases (HDAC) has beneficial effects in mouse models of muscular dystrophies indicating that HDACs are a potential pharmacological target for Duchenne Muscular Dystrophy (DMD). We have studied the effects of Givinostat, a potent HDAC inhibitor, on histological and functional parameters in mdx mice. Givinostat 1, 5 and 10 mg/kg ip was administered daily for 90 days to mdx mice that were 2 month old at the beginning of the treatment. Saline (SAL) and Trichostatin 0.6 mg/kg po (TSA) were administered as controls. Eight animals per group were treated. Motor function performance (treadmill) and body weight were measured at different time points. At the end of treatment quadriceps, tibialis anteriore and blood were collected for weight assessment, histological processing and pharmacokinetic measurements. Fibrosis (Masson's trichrome staining), inflammatory infiltration (Myeloperoxidase) and muscle cross sectional area (H&E staining) were measured on specimens of tibialis anteriore. Results were subjected to statistical analysis and pk-pd analysis. P values are versus SAL. A treatment effect was observed on body weight. Quadriceps weights were increased by Givinostat 5 and 10 mg/kg and TSA (p < 0.05). Givinostat dose dependently reduced fibrosis (p < 0.001 all doses), and inflammation (p < 0.05, 5 and 10 mg/kg). A trend shift towards larger diameter muscle fibres was observed with Givinostat 10 mg/kg. Givinostat 5 mg/kg improved treadmill preformance (p < 0.05 at 60 days). TSA increased quadriceps weight (p < 0.01) and reduced fibrosis (p < 0.001). The pk-pd analysis confirmed the relationship between Givinostat exposures and histological and functional effects and indicated that blood exposures of nearly 600 h nmol/L are needed to obtain the desired effects. This study in mdx mice shows a clear dose and/or concentration dependent effect on functional and histological parameters and supports the clinical development of Givinostat for the treatment of DMD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
