scholarly journals Differential Effects of a Full and Biased Ghrelin Receptor Agonist in a Mouse Kindling Model

2019 ◽  
Vol 20 (10) ◽  
pp. 2480 ◽  
Author(s):  
An Buckinx ◽  
Yana Van Den Herrewegen ◽  
Anouk Pierre ◽  
Eleonora Cottone ◽  
Khoubaib Ben Haj Salah ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Receptor Agonist ◽  
Full Agonist ◽  
Seizure Severity ◽  
Differential Effects ◽  
Ghrelin Receptor ◽  
Kindling Model ◽  
Potential Target ◽  
Ghrelin Receptor Agonist

The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and β-arrestin pathways. In this study, we aimed to deepen our understanding regarding signaling pathways downstream the ghrelin-R responsible for mediating anticonvulsive effects in a kindling model. Mice were administered the proconvulsive dopamine 1 receptor-agonist, SKF81297, to gradually induce a kindled state. Prior to every SKF81297 injection, mice were treated with a ghrelin-R full agonist (JMV-1843), a Gαq and Gα12 biased ligand unable to recruit β-arrestin (YIL781), a ghrelin-R antagonist (JMV-2959), or saline. Mice treated with JMV-1843 had fewer and less severe seizures compared to saline-treated controls, while mice treated with YIL781 experienced longer and more severe seizures. JMV-2959 treatment did not lead to differences in seizure severity and number. Altogether, these results indicate that the Gαq or Gα12 signaling pathways are not responsible for mediating JMV-1843′s anticonvulsive effects and suggest a possible involvement of β-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.

Integrated Approach to Early Detection of Cardiovascular Toxicity Induced by a Ghrelin Receptor Agonist

2015 ◽  
Vol 34 (2) ◽  
pp. 151-161 ◽  
Author(s):  
Alan H. Stokes ◽  
J. Greg Falls ◽  
Lawrence Yoon ◽  
Neal Cariello ◽  
Brenda Faiola ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Receptor Agonist ◽  
Troponin I ◽  
Troponin T ◽  
Heart Weight ◽  
Repeat Dose ◽  
End Points ◽  
Fatty Acid Binding ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist

Cardiovascular (CV) safety concerns are among the leading causes of compound attrition in drug development. This work describes a strategy of applying novel end points to a 7-day rodent study to increase the opportunity to detect and characterize CV injury observed in a longer term (ie, 28 days) study. Using a ghrelin receptor agonist (GSK894281), a compound that produces myocardial degeneration/necrosis in rats after 28 days at doses of 0.3, 1, 10, or 60 mg/kg/d, we dosed rats across a range of similar doses (0, 0.3, 60, or 150 mg/kg/d) for 7 days to determine whether CV toxicity could be detected in a shorter study. End points included light and electron microscopies of the heart; heart weight; serum concentrations of fatty acid-binding protein 3 (FABP3), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and N-terminal proatrial natriuretic peptide (NT-proANP); and a targeted transcriptional assessment of heart tissue. Histologic evaluation revealed a minimal increase in the incidence and/or severity of cardiac necrosis in animals administered 150 mg/kg/d. Ultrastructurally, mitochondrial membrane whorls and mitochondrial degeneration were observed in rats given 60 or 150 mg/kg/d. The FABP3 was elevated in rats given 150 mg/kg/d. Cardiac transcriptomics revealed evidence of mitochondrial dysfunction coincident with histologic lesions in the heart, and along with the ultrastructural results support a mechanism of mitochondrial injury. There were no changes in cTnI, cTnT, NT-proANP, or heart weight. In summary, enhancing a study design with novel end points provides a more integrated evaluation in short-term repeat dose studies, potentially leading to earlier nonclinical detection of structural CV toxicity.

scholarly journals Population pharmacokinetics (PPK) of anamorelin (ANAM), an oral selective ghrelin receptor agonist

2018 ◽  
Vol 29 ◽  
pp. viii616-viii617 ◽  
Author(s):  
A. Bernareggi ◽  
S. Kaasa ◽  
M. Fallon ◽  
R.J.E. Skipworth ◽  
D. Currow
Keyword(s):  
Population Pharmacokinetics ◽  
Receptor Agonist ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist

scholarly journals Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers

2016 ◽  
Vol 28 (11) ◽  
pp. 1705-1713 ◽  
Author(s):  
A. D. Nelson ◽  
M. Camilleri ◽  
A. Acosta ◽  
I. Busciglio ◽  
S. Linker Nord ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Receptor Agonist ◽  
Motor Functions ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist

Investigation of the effectiveness of a ghrelin receptor agonist to stimulate the defecation centre in spinal cord injured rats

2011 ◽  
Vol 163 (1-2) ◽  
pp. 58
Author(s):  
J.B. Furness ◽  
D.M. Ferens ◽  
M.D. Habgood ◽  
N.R. Saunders ◽  
D.J. Brown ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Receptor Agonist ◽  
Ghrelin Receptor ◽  
Ghrelin Receptor Agonist ◽  
Spinal Cord Injured

Ghrelin receptor agonist, GHRP-2, produces antinociceptive effects at the supraspinal level via the opioid receptor in mice

Peptides ◽  
2014 ◽  
Vol 55 ◽  
pp. 103-109 ◽  
Author(s):  
Ping Zeng ◽  
Shu Li ◽  
Yue-hui Zheng ◽  
Fu-Yan Liu ◽  
Jing-lei Wang ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Ghrelin Receptor ◽  
Antinociceptive Effects ◽  
Ghrelin Receptor Agonist

Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats

2020 ◽  
Author(s):  
Tayfun Baser ◽  
Ercan Ozdemir ◽  
Ahmet Kemal Filiz ◽  
Ahmet Sevki Taskiran ◽  
Sinan Gursoy
Keyword(s):  
Analgesic Activity ◽  
Receptor Agonist ◽  
Morphine Tolerance ◽  
Peptide Hormone ◽  
Tail Flick ◽  
Analgesic Tolerance ◽  
Ghrelin Receptor ◽  
Analgesic Effects ◽  
Ghrelin Receptor Agonist ◽  
Ghrelin Receptor Antagonist

Ghrelin is a peptide hormone released from the gastric endocrine glands and shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not been elucidated yet. The purpose of the study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [D-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adults rats (weighing approximately 220-240 g) were used in the experiments. To induce morphine tolerance a 3-day cumulative dose regimen was used in rats. Then, randomly selected rats were evaluated for morphine tolerance on day 4. The analgesic effects of hexarelin (0.2 mg/kg), [D-Lys3]-GHRP-6 (10 mg/kg), and morphine (5 mg/kg) were measured at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [D-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Besides, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.

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