Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats

Obay, Basra Deniz; Taşdemir, Ezel; Tümer, Cemıl; Bilgin, Hakkı Murat; Şermet, Abdurrahman

doi:10.1016/j.peptides.2007.04.003

Cited by 75 publications

(60 citation statements)

References 32 publications

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“…Data from human studies in this area are conflicting, with some studies concluding either increased [15,16] or decreased [17][18][19][20][21][22] plasma levels of ghrelin in epileptic patients. Rodent studies are more consistent, with the majority of studies indicating that ghrelin shows an anticonvulsant action in different models [10,[23][24][25], but its mechanism of action is unknown.…”

Section: Introductionmentioning

confidence: 84%

“…Cells were subcultured at 70 to 80 % confluency and re-suspended in 96-well plates at 60,000 cells per well. Concentrations of A778193 were added in quadruplicate to the cells and incubated for 90 minutes at 37°C in air/CO 2 (1-7), (1-9), (1-11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23)(24)(25)(26)(27)(28) were tested next to the GHSR agonist capromorelin. A sigmoidal dose response curve was fitted using GraphPad Prism software, GraphPad Software, (La Jolla, USA), yielding a pEC 50 and curve maximum.…”

Section: In Vitro Ghsr Inverse Agonism Determinationmentioning

confidence: 99%

“…Since it was hypothesized that ghrelin-induced elevations of the inhibitory neurotransmitter GABA could account for the anticonvulsant effect of ghrelin [25], we determined whether ghrelin induces extracellular GABA alterations in the hippocampus via in vivo microdialysis. Mean pooled baseline hippocampal GABA dialysate concentration (mean±SEM) was 0.05 ±0.01 μM (n09) (Fig.…”

Section: Hippocampal Extracellular Gaba Levels Are Not Altered After mentioning

confidence: 99%

“…Previous studies have shown that ghrelin has an inhibitory effect on seizures induced by pentylenetetrazole [25], penicillin [23], and kainic acid [10], but its anticonvulsant mechanism of action remains elusive. Ghrelin was shown in an ex vivo study to possess neuroprotective effects associated with the promotion of phosphoinositide-3-kinase (PI3K)/Akt signaling pathway and the inhibition of the mitochondrial-dependent apoptosis pathway [11].…”

Section: Ghrelin Is Anticonvulsant In In Vivo and In Vitro Models Andmentioning

confidence: 99%

“…The effect of ghrelin on GABA release [39] has been proposed as a possible mechanism of action of the anticonvulsant effects of ghrelin [10,23,25]. However, these ghrelin-GABA interactions were only described in the hypothalamic circuitry and not in the cortical or thalamic brain regions, which are mainly involved in the generation of pentylenetetrazole-induced seizures [40].…”

Section: Ghrelin Is Anticonvulsant In In Vivo and In Vitro Models Andmentioning

confidence: 99%

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Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.

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Section: Introductionmentioning

confidence: 84%

Section: In Vitro Ghsr Inverse Agonism Determinationmentioning

confidence: 99%

Section: Hippocampal Extracellular Gaba Levels Are Not Altered After mentioning

confidence: 99%

Section: Ghrelin Is Anticonvulsant In In Vivo and In Vitro Models Andmentioning

confidence: 99%

Section: Ghrelin Is Anticonvulsant In In Vivo and In Vitro Models Andmentioning

confidence: 99%

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Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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Identification of a Putative β‐Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR)

et al. 2021

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Ghrelin is a pleiotropic feeding hormone which also has a pivotal role in the central nervous system. Upon the activation of its receptor, growth hormone secretagogue receptor (GHSR), the Gαq/11‐mediated and the β‐arrestin‐mediated signaling pathways are activated. As the β‐arrestin pathway is a potential drug target, there is a strong need for β‐arrestin‐biased GHSR modulators. Activation of the β‐arrestin pathway should inhibit the Gαq/11‐mediated calcium flux through internalization of the receptor. Hence, we used the antagonistic activity in the calcium assay as the first screening for the β‐arrestin activation. By conducting the second screening assay for the β‐arrestin activation based on extracellular signal regulated kinase (ERK) 1/2 phosphorylation, we discovered a putative β‐arrestin‐biased superagonist. The activity of the compound was not completely blocked with the competitive antagonist, which implies that the effect is mediated, at least partly, by allosteric binding of the compound.

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