Cabergoline, a dopamine receptor agonist, has an antidepressant-like property and enhances brain-derived neurotrophic factor signaling

Chiba, Shuichi; Numakawa, Tadahiro; Ninomiya, Midori; Yoon, Hyung Shin

doi:10.1007/s00213-010-1894-8

Cited by 33 publications

(19 citation statements)

References 62 publications

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“…Down-stream, cabergoline increases expression and signaling of brain-derived neurotrophic factor (BDNF). BDNF is one of the most important suppressors of food intake, and BDNF is low in PWS (80, 81). …”

Section: Implications Of Ghsr1:drd2 Heteromers In Obsessive Eating Asmentioning

confidence: 99%

Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain

2014

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The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a) is expressed mainly in the central nervous system (CNS). In this review, we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a), we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review, we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2) and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader–Willi syndrome (PWS). GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively, enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with PWS. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance.

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Section: Implications Of Ghsr1:drd2 Heteromers In Obsessive Eating Asmentioning

confidence: 99%

Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain

2014

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“…Cabergoline, an ergot derivative that causes delusions , is a dopamine agonist that has an antidepressant-like property [31]. The dopamine receptor agonist pergolide has shown antidepressant effects in Parkinson patients [32].…”

Section: Resultsmentioning

confidence: 99%

Systematic Drug Repositioning Based on Clinical Side-Effects

2011

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Drug repositioning helps fully explore indications for marketed drugs and clinical candidates. Here we show that the clinical side-effects (SEs) provide a human phenotypic profile for the drug, and this profile can suggest additional disease indications. We extracted 3,175 SE-disease relationships by combining the SE-drug relationships from drug labels and the drug-disease relationships from PharmGKB. Many relationships provide explicit repositioning hypotheses, such as drugs causing hypoglycemia are potential candidates for diabetes. We built Naïve Bayes models to predict indications for 145 diseases using the SEs as features. The AUC was above 0.8 in 92% of these models. The method was extended to predict indications for clinical compounds, 36% of the models achieved AUC above 0.7. This suggests that closer attention should be paid to the SEs observed in trials not just to evaluate the harmful effects, but also to rationally explore the repositioning potential based on this “clinical phenotypic assay”.

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“…Neurotrophic factors evoke ERK activation and promote proliferation, differentiation, neurite outgrowth and survival, while stress stimuli induce ERK activation that mediates cell death [38]–[43]. Here, we first examined whether cabergoline increased the expression of BDNF as we previously reported that upregulation of BDNF in hippocampal tissues by cabergoline [21]. Furthermore, BDNF has neuroprotective effects via the activation of Akt and ERK signaling [38].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, cabergoline could also affect these brain regions. Indeed, we previously reported that cabergoline increases hippocampal brain-derived neurotrophic factor (BDNF, an important regulator in the synaptic plasticity) and exerts an antidepressant effect in rats [21], [22], suggesting a beneficial effect of cabergoline on neuronal populations other than those in the mesencephalon. In the present study, we investigated the neuroprotective effect of cabergoline against oxidative stress caused by H 2 O 2 in cultured cortical neurons, and found that significant neuroprotection occurred by a D 2 receptor-mediated mechanism.…”

Section: Introductionmentioning

confidence: 99%

Cabergoline, Dopamine D2 Receptor Agonist, Prevents Neuronal Cell Death under Oxidative Stress via Reducing Excitotoxicity

et al. 2014

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Several lines of evidence demonstrate that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease. Potent antioxidants may therefore be effective in the treatment of such diseases. Cabergoline, a dopamine D2 receptor agonist and antiparkinson drug, has been studied using several cell types including mesencephalic neurons, and is recognized as a potent radical scavenger. Here, we examined whether cabergoline exerts neuroprotective effects against oxidative stress through a receptor-mediated mechanism in cultured cortical neurons. We found that neuronal death induced by H2O2 exposure was inhibited by pretreatment with cabergoline, while this protective effect was eliminated in the presence of a dopamine D2 receptor inhibitor, spiperone. Activation of ERK1/2 by H2O2 was suppressed by cabergoline, and an ERK signaling pathway inhibitor, U0126, similarly protected cortical neurons from cell death. This suggested the ERK signaling pathway has a critical role in cabergoline-mediated neuroprotection. Furthermore, increased extracellular levels of glutamate induced by H2O2, which might contribute to ERK activation, were reduced by cabergoline, while inhibitors for NMDA receptor or L-type Ca2+ channel demonstrated a survival effect against H2O2. Interestingly, we found that cabergoline increased expression levels of glutamate transporters such as EAAC1. Taken together, these results suggest that cabergoline has a protective effect on cortical neurons via a receptor-mediated mechanism including repression of ERK1/2 activation and extracellular glutamate accumulation induced by H2O2.

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Cabergoline, a dopamine receptor agonist, has an antidepressant-like property and enhances brain-derived neurotrophic factor signaling

Abstract: Cabergoline exerts antidepressant- and anxiolytic-like effects, which may be mediated by potentiation of intracellular signaling of BDNF.

Cited by 33 publications

References 62 publications

Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain

Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain

Systematic Drug Repositioning Based on Clinical Side-Effects

Cabergoline, Dopamine D2 Receptor Agonist, Prevents Neuronal Cell Death under Oxidative Stress via Reducing Excitotoxicity

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