ABSTRACT
Aim To explore the differences of pathogenesis for the hepatotoxicity induced by chronic treatment of valproic acid(VPA) in different ages,and in combination administration with inducers of liver enzyme.Methods Animal models were established by oral administration chronically with VPA at doses of 200 or 500 mg?kg~(-1) per day in 30 days for 50 Wistar rats(infant and adult rats) with inducers of liver enzyme Phenobarbital(PB) or not.Mitochondria were obtained by differential centrifugation.Levels of liver enzymes,coagulation factors,plasma ammonia,VPA and PB serum levels,and L-carnitine in sera,as well as the changes of respiratory enzymes and lipid peroxidation in hepatic mitochondria were measured.Mitochondrial membrane potential(MMP) and mRNA expression of CYP450 reductase in liver were determined by flow cytometer and in situ hybridization,and morphological changes of hepatocytes were observed under microscope with Oil-Red-O staining.Results ① In all rats treated with higher dose of VPA added with PB or not,there were no significant elevations of liver enzymes(ALT and AST).However significant abnormalities of function of blood coagulation and serum fibrinogen were shown, and the levels of plasma ammonia and L-carnitine were also changed significantly,and the changes were notable in infant rats or in those rats added with PB. ② Average contents of cytochrome aa3 in liver mitochondria of infant rats were reduced by 58.80% and 61.80% because of administration of high dose VPA and high dose VPA added with PB,but were reduced by 37.55% and 46.53% in adults.As for activities of SDH,which affected by high dose VPA in infants,were significant decreased by 44.8% and 57.9%,respectively,but still in normal range in adult groups.Activities of CCO in liver mitochondria were significantly lowered by high dose VPA or added with PB compared with controls(P
ABSTRACT
Objective:To explore the protective function of L-carnitine against valproate-associated hepatotoxicity in infant rats and its mechanism.Methods:Rat models with VPA liver lesion were established by oral administration of VPA and PB.L-carnitine was adopted as intervention measure:to observe its protection of experiment rat livers,especially the function of liver mitochondrion.Levels of plasma ammonia,L-carnitine and coagulation factors in sera as well as the changes of respiratory enzymes in hepatic mitochondria were measured by chemical colorimetry. Mitochondrial membrane potential(MMP),and VPA and PB blood drug levels in liver were determined by flow cytometer and HPLC,respectively.and morphological changes of hepatocytes were observed under microscope with Oil-Red-O staining.Results(1)In the groups affected by VPA or VPA added with PB,the activities of SDH and CCO significantly decreased compared with control group(P
ABSTRACT
Objective To explore the effect of chronic low lead exposure on molecular pathological mechanisms of learning and memory of rats at the developmental stage Methods The changes of N methyl D aspartate receptor 1 (NMDAR 1) mRNA expression in rat hippocampus were observed by using digoxigenin labled anti sense oligonucleotide probes in situ hybridization technique Results The changes in NMDAR 1 mRNA levels in Pb exposed rat hippocampus were found to be dependent upon the developmental period of exposure and the region of the hippocampus analyzed Hippocampal NMDAR 1 mRNA levels increased significantly in the CA1 (18 75%) and CA3 (13 2%) ( P