动物造模 z-bio 2022-09-26 664

　　OBJECTIVE: To evaluate the cardiotoxicity of the drug sibutramine using two cardiac-specific CYP2E1 gene-modified mice, and to select an animal model with higher sensitivity in evaluating the cardiotoxicity of the drug.

　　Methods: 8-week-old male Tg(+) mice, sTg(+) mice, and wild-type C57BL/6 mice (WT), 50 mice in each group, were randomly divided into 5 groups, 10 mice in each group, and vehicle control group (gavage with purified drinking water) and 4 experimental groups (50, 100, 150, 300 mg/kg sibutramine). General symptom observation and survival rate measurement were carried out during the administration; Blood was collected and the heart was dissected, and the blood biochemical cardiac injury indexes of the experimental mice in each group were determined: lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB). The expression of connexin 43 (CX43) in cardiac tissue was observed by immunohistochemistry.

　　Results: (1) The blood biochemical indexes showed that the Tg(+) mice were significantly higher than the WT mice at the dosage of 50 mg/kg and 100 mg/kg (P<0.05 or P<0.01); At doses of 50, 100 and 150 mg/kg, Tg(+) mice were significantly higher than sTg(+) mice (P<0.05 or P<0.01); kg, Tg(+) mice were significantly lower than WT and sTg(+) mice (P<0.05 or P<0.01), and sTg(+) mice had the smallest reduction. (2) Histopathological results showed that Tg(+) and WT mice showed signs of heart damage in each administration group. (3) Immunohistochemical staining showed that with the increase of administration dose, Tg(+), Tg(+), The expression of CX43 in the intercalated discs of cardiomyocytes in sTg(+) and WT mice gradually decreased, and the staining color gradually became lighter; while the expression of CX43 in the intercalated disks of cardiomyocytes decreased and the staining color became lighter. The degree from high to low was Tg(+) mice, followed by WT mice and sTg(+) mice.

　　Conclusion: Tg(+) mice may have higher sensitivity than WT mice in evaluating the potential cardiotoxicity of drugs, and sTg(+) mice are good cardiotoxicity protection models.