The Protective Effect Of Histone Deacetylase Inhibitor ACY1215 On Brain Edema Of Acute Liver Failure In Mice

Objective:To explore the protective effect of ACY1215 as a selective histone deacetylase 6(HDAC6)inhibitor on brain edema of acute liver failure(ALF)in mice.Methods:A combination of lipopolysaccharide(LPS)and D-galactosamine(D-Gal)was used to induce ALF animal model in mice.ACY1215 were administered 2 hours prior to D-Gal and LPS injection in mice.After treatment,the liver histologic analysis and levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),serum ammonia,tumor necrosis factor alpha(TNF-a)and interferon gamma(IFN-y)were also observed.The percentage brain water content was determined using the wet-dry method.The blood brain barrier(BBB)integrity and permeability was assessed by transmission electron microscope.Western blotting were used to determine the expression of NF-?B-p65,histone,and acetylation of histone in brain respectively.The gene expression of inflammatory factor TNF-a was also detected by polymerase chain reaction(PCR).Results:The serum levels of ALT,AST,ammonia,TNF-a and IFN-y were significantly increased in ALF mice(P<0.05).But ACY1215 reduced the serum up levels of ALT,AST,ammonia,TNF-a and IFN-y in model group(P<0.05).The severe liver histopathological injury in ALF was improved in ACY1215-treated group.Moreover,it also inhibited NF-?B-p65 protein(P<0.05),suppressed the mRNA levels of TNF-a(P<0.05),and alleviated brain water content in ALF(P<0.05).The subtle BBB alterations were observed in model mice,and the alterations were alleviated in ACY1215-treated group.The acetylated histone H3 and H4 were increased in model group(P<0.05),and the ACY1215 further enhanced the acetylation of histone H3 and H4(P<0.05).Conclusions:ACY1215 alleviates brain edema in ALF through regulating the acetylation of histone to suppress inflammation.