Liraglutide prevents metabolic side-effects and improves recognition and working memory during antipsychotic treatment in rats

Babic, Ilijana; Gorak, Ashleigh; Engel, Martin; Sellers, Dominic; Else, Paul L.; Osborne, Ashleigh L.; Pai, Nagesh B; Huang, Xu‐Feng; Nealon, Jessica R.; Weston–Green, Katrina

doi:10.1177/0269881118756061

Cited by 31 publications

(25 citation statements)

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“…The present study is a continuation of our previous publication (Babic et al, 2018). Briefly, female Sprague Dawley rats ( n = 72, weighing 200–225 g; Animal Resources Centre, Perth, Australia) were individually housed at 22°C on corn cob bedding with plastic tunnels and nesting material for environmental enrichment.…”

Section: Methodssupporting

confidence: 59%

“…; Zyprexa; Eli Lilly, Indianapolis, IN) via oral cookie dough pellet, clozapine (12 mg/kg t.i.d., Clozaril; Norvatis, Basel, Switzerland) via oral cookie dough pellet, olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (oral cookie dough pellet without drug + SC sterile water; n = 12/group) for six weeks. Olanzapine and clozapine tablets were de-coated and pulverised, and the assigned dosage was added to a cookie dough mixture, as previously detailed (Babic et al, 2018; Weston-Green et al, 2011). A cookie dough pellet (0.3 g) was offered on a metal spoon, and rats were monitored to ensure consumption of each pellet.…”

Section: Methodsmentioning

confidence: 99%

“…Preclinical studies have shown that liraglutide can treat weight gain and restore glucose homeostasis in olanzapine-treated rats with established obesity and T2DM (Lykkegaard et al, 2008). Our lab reported that liraglutide prevents olanzapine-induced weight gain and clozapine-induced hyperglycaemia side effects in rats when administered from the start of APD treatment (Babic et al, 2018). However, the mechanisms underlying the efficacy of liraglutide remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

et al. 2021

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Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms. Aim: This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia. Methods: In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed. Results: Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels. Conclusion: The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.

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Section: Methodssupporting

confidence: 59%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

et al. 2021

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“…The use of preclinical paradigms offers the additional benefit of helping to disentangle the multifactorial causes of metabolic dysregulation in psychiatric illness, where variables such as diet, exercise, and drug use can all contribute to cardiometabolic dysregulation (25)(26)(27). Fortunately, the past 10-15 years has seen significant advances in animal models of the metabolic side-effects of antipsychotic drugs (28), which have demonstrated that many of these compounds cause acute glucose dysregulation and insulin resistance independent of weight gain (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Acute Treatment With Antipsychotic Drugs on Peripheral Catecholamines

Boyda

Tse

et al. 2020

Front. Psychiatry

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Antipsychotic drugs represent the most effective treatment for chronic psychotic disorders. The newer second generation drugs offer the advantage of fewer neurological side-effects compared to prior drugs, but many cause serious metabolic side-effects. The underlying physiology of these side-effects is not well-understood, but evidence exists to indicate that the sympathetic nervous system may play an important role. In order to examine this possibility further, we treated separate groups of adult female rats acutely with either the first generation antipsychotic drug haloperidol (0.1 or 1 mg/kg) or the second generation drugs risperidone (0.25 or 2.5 mg/kg), clozapine (2 or 20 mg/kg), olanzapine (3 or 15 mg/kg) or vehicle by intraperitoneal injection. Blood samples were collected prior to drug and then 30, 60, 120, and 180 mins after treatment. Plasma samples were assayed by HPLC-ED for levels of norepinephrine, epinephrine, and dopamine. Results confirmed that all antipsychotics increased peripheral catecholamines, although this was drug and dose dependent. For norepinephrine, haloperidol caused the smallest maximum increase (+158%], followed by risperidone (+793%), olanzapine (+952%) and clozapine (+1,684%). A similar pattern was observed for increases in epinephrine levels by haloperidol (+143%], olanzapine (+529%), risperidone (+617%) then clozapine (+806%). Dopamine levels increased moderately with olanzapine [+174%], risperidone [+271%], and clozapine [+430%]. Interestingly, levels of the catecholamines did not correlate strongly with each other prior to treatment at baseline, but were increasingly correlated after treatment as time proceeded. The results demonstrate antipsychotics can potently regulate peripheral catecholamines, in a manner consistent with their metabolic liability.

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“…Moreover, liraglutide exerts positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control in the clinic. Thus, many studies have investigated its effects on the cardiovascular, endocrine, and nervous systems (Ishii et al, 2017;Babic et al, 2018;Bahtiyar et al, 2018). In animal models and clinical patients, there were no adverse events or reproductive toxicity found posttreatment with liraglutide.…”

Section: Discussionmentioning

confidence: 99%

Treatment With Liraglutide Exerts Neuroprotection After Hypoxic–Ischemic Brain Injury in Neonatal Rats via the PI3K/AKT/GSK3β Pathway

Zeng

Bai

Jiang

et al. 2020

Front. Cell. Neurosci.

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Neonatal hypoxic-ischemic (HI) brain injury is a detrimental disease, which results in high mortality and long-term neurological deficits. Nevertheless, the treatment options for this disease are limited. Thus, the aim of the present study was to assess the role of liraglutide in neonatal HI brain injury in rats and investigate the associated mechanisms. The results showed that treatment with liraglutide significantly reduced infarct volume and ameliorated cerebral edema, decreased inflammatory response, promoted the recovery of tissue structure, and improved prognosis following HI brain injury. Moreover, treatment with liraglutide inhibited apoptosis and promoted neuronal survival both in the rat model and following oxygen-glucose deprivation (OGD) insult. LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), partially reversed these therapeutic effects, suggesting that the PI3K/protein kinase B (Akt) pathway was involved. In conclusion, our data revealed that treatment with liraglutide exerts neuroprotection after neonatal HI brain injury via the PI3K/Akt/glycogen synthase kinase-3β (GSK3β) pathway and may be a promising therapy for this disease.

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Liraglutide prevents metabolic side-effects and improves recognition and working memory during antipsychotic treatment in rats

Cited by 31 publications

References 97 publications

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats

Differential Effects of Acute Treatment With Antipsychotic Drugs on Peripheral Catecholamines

Treatment With Liraglutide Exerts Neuroprotection After Hypoxic–Ischemic Brain Injury in Neonatal Rats via the PI3K/AKT/GSK3β Pathway

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