Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats  

作　　者：De-juan Li Qin Yue Lu Liu Ke-ke Che Xue-mei Liu Chang-hua Hu 

机构地区：[1]College of Pharmaceutical Sciences,Medical Research Institute,Southwest University,Chongqing 400715,China [2]School of Medical Sciences,North Sichuan Medical College,Nanchong 637000,China

出　　处：《Acta Pharmacologica Sinica》2021年第8期1267-1279,共13页中国药理学报（英文版）

基　　金：financially supported by grants by Chongqing Natural Science Foundation,China(cstc2020jcyj-msxmX0424);Venture&Innovation Support Program for Chongqing Overseas Returnees(cx2018089).

摘　　要：Brexpiprazole(Bre)is a new multi-target antipsychotic drug(APD)approved by the US FDA in 2015,and shows good therapeutic potential.But it lacks assessments on the metabolic side effects,which obstructs the treatment of schizophrenia.Glucagon-like peptide 1(GLP1),an incretin associated with insulin action and metabolism,is involved in the metabolic syndrome(MS)caused by most APDs.In this study,we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS.In the first part of experiments,rats were orally administered Bre(0.5 mg·kg^(-1)·d^(-1))for 28 days with aripiprazole(1.0 mg·kg^(-1)·d^(-1))or olanzapine(1.0 mg·kg^(-1)·d^(-1))as the controls.Compared to vehicle,Bre administration significantly increased the weight gain,serum lipid(TG,TC,LDL,FFA),and blood glucose levels accompanied by the hormonal(insulin,glucagon,GLP1)imbalance,and the impaired glucose tolerance and insulin sensitivity.Moreover,we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα,AMPK,and β-catenin;Bre administration also caused islet dysfunction with decreased GLP1R,PI3K,IRβexpression in pancreas,and the interference of IRS1,PI3K,p-AKT,and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance.In the second part of experiments,rats were orally administered Bre(0.5 mg·kg^(-1)·d^(-1))for 42 days.We showed that co-administration with the GLP1 receptor(GLP1R)agonist liraglutide(0.125 mg·kg^(-1)·d^(-1),ip)could ameliorate Bre-caused metabolic abnormalities.Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.

关 键 词：SCHIZOPHRENIA brexpiprazole glycolipid metabolic disorder insulin resistance GLP1/GLP1R signaling LIRAGLUTIDE 

分 类 号：R965[医药卫生—药理学]