Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers

Lee, Mary R.; Farokhnia, Mehdi; Cobbina, Enoch; Saravanakumar, Anitha; Li, Xiaobai; Battista, Jillian T.; Farinelli, Lisa A.; Akhlaghi, Fatemeh; Leggio, Lorenzo

doi:10.1016/j.neuropharm.2019.107788

Cited by 22 publications

(18 citation statements)

References 28 publications

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“…Finally, the role of the ghrelin receptor constitutive activity reported in this work should be taken into account when considering its inverse agonists as anti-obesity agents (57), or their use for the treatment of alcohol use disorder (35,36). The novel object recognition task was adapted from Leger and colleagues (41), the object displacement test was adapted from Oliveira and colleagues (42) and the elevated plus maze was performed according to (58) .…”

Section: Discussionmentioning

confidence: 99%

“…Here, using a combination of imaging, biochemical and electrophysiological approaches, and behavior analysis, we uncover a role for the constitutive activity of the ghrelin receptor in providing tonic control for the regulation of AMPA receptor traffic, influencing synaptic plasticity in the hippocampus and interfering with learning and memory in vivo. These finding should be taken into account given that inverse agonists of the ghrelin receptor are presently being tested in humans to treat alcohol use disorder (35,36).…”

Section: Introductionmentioning

confidence: 99%

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Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation

Ribeiro

Catarino

Carvalho

et al. 2020

Preprint

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The ability of animals to store and retrieve food caches in the wild requires the integration of biological signals of hunger, satiety and memory. The role of ghrelin in regulating feeding and memory makes ghrelin receptors an important target to shape the required cellular and molecular responses. We investigated the effects of the high ligand-independent activity of the ghrelin receptor on the physiology of excitatory synapses. Blocking this type of activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Impaired constitutive activity from the ghrelin receptor increased surface diffusion of AMPA receptors and impaired AMPA receptor synaptic delivery mediated by chemical long-term potentiation. These observations support a role for the constitutive activity of the ghrelin receptor in regulating AMPA receptor trafficking under basal conditions and synaptic plasticity. Accordingly, we found that blocking the ghrelin receptor constitutive activity impairs spatial and recognition memory.Impact statementThis work uncovers a role for the constitutive activity of the ghrelin receptor in memory, and in the regulation of the synaptic levels of AMPA receptors, their mobility and synaptic plasticity. Underscoring the importance of deciphering the physiological role of constitutive ghrelin receptor activity, ghrelin receptor inverse agonism is now being considered as a therapy to treat alcohol use disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation

Ribeiro

Catarino

Carvalho

et al. 2020

Preprint

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“…One of the most obvious but relatively unaddressed issues is that of sex differences. For instance, phase 1a/b clinical trials of the inverse GHSR-1A agonist PF-5190457 have recently been reported (Denney et al, 2017 ; Lee et al, 2020a , b ). Although the drug appears promising, only one woman was included in these trials, albeit only a small study population was included in these reports.…”

Section: Appetite-regulatory Peptides In Substance Use Disordermentioning

confidence: 99%

“…PF-5190457 is the first orally bioavailable GHSR-1A inverse agonist to proceed into clinical development (Bhattacharya et al, 2014 ). In the initial phase 1a/b trial, it appeared well-tolerated in both healthy individuals and AUD patients (Denney et al, 2017 ; Lee et al, 2020a , b ) and reduced self-reported alcohol cue-elicited craving in a bar-like environment (Lee et al, 2020b ). However promising, the small study population should be noted, as well as the fact that only one female was included.…”

Section: Appetite-regulatory Peptides In Substance Use Disordermentioning

confidence: 99%

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

2021

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There is a substantial need for new pharmacological treatments of addiction, and appetite-regulatory peptides are implied as possible candidates. Appetite regulation is complex and involves anorexigenic hormones such as glucagon-like peptide-1 (GLP-1) and amylin, and orexigenic peptides like ghrelin and all are well-known for their effects on feeding behaviors. This overview will summarize more recent physiological aspects of these peptides, demonstrating that they modulate various aspects of addiction processes. Findings from preclinical, genetic, and experimental clinical studies exploring the association between appetite-regulatory peptides and the acute or chronic effects of addictive drugs will be introduced. Short or long-acting GLP-1 receptor agonists independently attenuate the acute rewarding properties of addictive drugs or reduce the chronic aspects of drugs. Genetic variation of the GLP-1 system is associated with alcohol use disorder. Also, the amylin pathway modulates the acute and chronic behavioral responses to addictive drugs. Ghrelin has been shown to activate reward-related behaviors. Moreover, ghrelin enhances, whereas pharmacological or genetic suppression of the ghrelin receptor attenuates the responses to various addictive drugs. Genetic studies and experimental clinical studies further support the associations between ghrelin and addiction processes. Further studies should explore the mechanisms modulating the ability of appetite-regulatory peptides to reduce addiction, and the effects of combination therapies or different diets on substance use are warranted. In summary, these studies provide evidence that appetite-regulatory peptides modulate reward and addiction processes, and deserve to be investigated as potential treatment target for addiction.

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“…Based on a significant number of encouraging preclinical results, ghrelin/GHS-R1A antagonism was suggested as a novel treatment approach for alcohol addiction therapy and recently, the first GHS-R1A-related compound was tested in initial human laboratory studies. The GHS-R1A-inverse agonist (PF5190457) was found to be well-tolerated and safe in healthy volunteers [ 96 ], and in a single-blind, within-subject, placebo controlled human laboratory study in heavy alcohol drinkers, it was found to significantly reduce the alcohol cue-induced craving in comparison to the placebo, while the safety/tolerability assessment revealed only mild or moderate adverse events, which did not require the discontinuation or dose reduction of the PF5190457 [ 71 , 97 ]. A robust tow-compartment model describing the pharmacokinetic characteristics of PF5190457 has been created [ 98 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

Sustkova-Fiserova

Charalambous

Khryakova

et al. 2022

IJMS

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Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin’s/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin’s/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

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Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers

Cited by 22 publications

References 28 publications

Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation

Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

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