Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

被引:47
作者
Lian, Jiamei [1 ,2 ]
Huang, Xu-Feng [1 ,2 ]
Pai, Nagesh [2 ]
Deng, Chao [1 ,2 ]
机构
[1] Illawarra Hlth & Med Res Inst, Wollongong, NSW 2522, Australia
[2] Univ Wollongong, Sch Med, Wollongong, NSW 2522, Australia
基金
英国医学研究理事会;
关键词
Betahistine; Antipsychotic drug; Histamine receptor; Weight gain; Locomotor activity; Therapeutic efficacy; HISTAMINE H-1 RECEPTOR; ACTIVATED PROTEIN-KINASE; CORTICOTROPIN-RELEASING HORMONE; OLANZAPINE-INDUCED HYPERPHAGIA; HYPOTHALAMIC ARCUATE NUCLEUS; ADIPOSE-TISSUE THERMOGENESIS; DIET-INDUCED OBESITY; NEUROPEPTIDE-Y; FOOD-INTAKE; ENERGY-BALANCE;
D O I
10.1016/j.phrs.2016.02.011
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H-1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H-3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naive patients with schizophrenia, as well as in the animal models of both drug-naive rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPK alpha (NPY: neuropeptide Y; AMPK alpha: AMP-activated protein kinase alpha) pathways, and ameliorate olanzapine-induced dyslipidaemia through modulation of AMPK alpha-SREBP-1-PPAR alpha-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPAR alpha: Peroxisome proliferator-activated receptor-alpha) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D-2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D-2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders. (C) 2016 Elsevier Ltd. All rights reserved.
引用
收藏
页码:51 / 63
页数:13
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