Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways

Lian, Jiamei; Huang, Xu‐Feng; Pai, Nagesh B; Deng, Chao

doi:10.1016/j.psyneuen.2014.06.010

Cited by 56 publications

(59 citation statements)

References 43 publications

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“…In hypothalamic tissue slices, the level of pAMPK can be enhanced markedly by olanzapine, which indicates that the weight gain/obesity side-effects associated with olanzapine is mediated by activation of hypothalamic AMPK linked to blockade of the histaminergic H 1 R [63]. Further in vivo studies in a rat model showed that the pAMPK level was upregulated by olanzapine administration correlated with changes in weight gain [56,64,65]. Additionally, administration of olanzapine by acute ICV infusion increased hypothalamic pAMPK expression [98,99].…”

Section: The Role Of Hypothalamic H 1 R-ampk Signalling In Sga-inducementioning

confidence: 93%

“…Several animal studies found that olanzapine could modulate histaminergic neurotransmission for the regulation of food intake and weight gain in rats [62,56,63]. Olanzapine treatment upregulated mRNA expression and protein levels of hypothalamic H 1 R, which was correlated with hyperphagia and weight gain induced by olanzapine [56,64,65]. Similarly, clinical studies demonstrated patients treated with antipsychotics showed a significant correlation between the genetic variants of H 1 R (rs346074 -rs346070), BMI (body mass index) and obesity [66,67].…”

Section: H 1 R H 3 R and Sga-induced Weight Gainmentioning

confidence: 96%

“…Since histamine cannot pass the blood-brain barrier, direct peripheral H 1 R antagonism by SGA treatment may also contribute to the obesity side-effects [13,56,64]. The H 1 R antagonistic affinity of SGAs is significantly correlated not only with increased body weight and adiposity, but also with insulin-resistance in schizophrenia patients [68,60,69].…”

Section: H 1 R H 3 R and Sga-induced Weight Gainmentioning

confidence: 99%

“…Several studies systematically investigated the mechanisms of olanzapine and betahistine cotreatment on attenuating olanzapine-induced weight gain in the rat brain using both drugnaïve and chronic animal models [64,65,75]. In detail, the study using olanzapine-naïve rats with 2 weeks' treatment found that co-treatment of O+B reversed the enhanced H 1 R and AMPK expression induced by olanzapine treatment ( Figure 2B) [64].…”

Section: The Mechanisms Underlying Betahistine In Reducing Antipsychomentioning

confidence: 99%

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

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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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 H1 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 H3 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-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve 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-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) 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 D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 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.

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Section: The Role Of Hypothalamic H 1 R-ampk Signalling In Sga-inducementioning

confidence: 93%

Section: H 1 R H 3 R and Sga-induced Weight Gainmentioning

confidence: 96%

Section: H 1 R H 3 R and Sga-induced Weight Gainmentioning

confidence: 99%

Section: The Mechanisms Underlying Betahistine In Reducing Antipsychomentioning

confidence: 99%

See 2 more Smart Citations

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

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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“…In addition, abnormal expression of NRG1 and ErbB4 has been identified in the PFC and hippocampus of schizophrenia patients (Chong et al, 2008;Law et al, 2006). In brief, 500m thickness fresh frozen brain was cut at -14 º C and collected on glass slides (Lian et al, 2014a, c;Zhang et al, 2014). Identified using a standard rat brain atlas (Paxinos and Watson, 1997), the PFC (Bregma 4.68mm to 2.76mm), Cg (Bregma 2.28mm to -0.36mm) and hippocampus (Bregma -2.28mm to -5.40mm) were collected bilaterally using a microdissection puncher.…”

Section: Western Blottingmentioning

confidence: 99%

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

Deng

Pan

et al. 2015

Psychiatry Research

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Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Postmortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short-or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.5 mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135 kDa, 70 kDa and 40 kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70 kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70 kDa and -40 kDa in the cingulate cortex (Cg), and NRG1-135 kDa, -70 kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135 kDa in the PFC, NRG1-40 kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40 kDa in the PFC and Cg was also downregulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia. AbstractNeuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short-or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75mg/kg), haloperidol (0.1mg/kg), olanzapine (0.5mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135kDa, 70kDa and 40kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70kDa and -40kDa in the cingulate cortex (Cg), and NRG1-135kDa, -70kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135kDa in the PFC, NRG1-40kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and regionspecific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia.

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Histamine and Appetite

Provensi

Blandina

Passani

2016

Histamine Receptors

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Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways

Cited by 56 publications

References 43 publications

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

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

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

Histamine and Appetite

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