Beneficial effects of desacyl-ghrelin, hexarelin and EP-80317 in models of status epilepticus

Biagini, Giuseppe; Torsello, Antonio; Marinelli, Carlo; Gualtieri, Fabio; Vezzali, Riccardo; Coco, Silvia; Bresciani, Elena; Locatelli, Vittorio

doi:10.1016/j.ejphar.2011.08.020

Cited by 32 publications

(60 citation statements)

References 41 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%

“…Thus, we confirmed our hypothesis by testing the ghrelin (1-5) amide in vivo, where we revealed for the first time that it is desensitization and not activation of the GHSR that is necessary to attenuate limbic seizures in vivo. 50 and pDC 50 of Ghrelin, Ghrelin Fragments (1-5) Amide, (1-7), (1-9), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), (23)(24)(25)(26)(27)(28) Ghrelin and capromorelin similarly activated and desensitized the growth hormone secretagogue receptors (GHSRs). The truncated forms of ghrelin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and (1-5) amide had a similar activity (pEC 50…”

Section: Receptor Desensitization Induced By Ghrelinmentioning

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: Receptor Desensitization Induced By Ghrelinmentioning

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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“…The inhibitory effect of ghrelin appears to be associated with the reduction in matrix metalloproteinase-3 expression in damaged hippocampal neurons [104]. Furthermore, recent findings demonstrate that desacyl-ghrelin, hexarelin and EP-80317 ligands display relevant anticonvulsive properties in models of limbic seizures [108]. In the hippocampus, Lep activates the PI 3 K/Akt, JAK STAT, and AMK/SIRT pathways, thus promoting neuronal survival, BACE1 down-regulation, reducing Aβ production and increasing its clearance, and reducing Tau phosphorylation.…”

Section: Leptin and Inflammationmentioning

confidence: 97%

The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin

et al. 2015

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“…Furthermore, ghrelin attenuated kainic acid-induced neuronal cell death in the mouse hippocampus [219] and protected hippocampal neurons in pilocarpine-induced seizures of rats by inhibiting cell apoptosis [220]. In turn, another study suggested that only des-acylated ghrelin is beneficial in hippocampal seizures [221]. Different mechanisms of action were suggested for ghrelin action on seizures and its neuroprotective actions.…”

Section: Ghrelinmentioning

confidence: 99%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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Beneficial effects of desacyl-ghrelin, hexarelin and EP-80317 in models of status epilepticus

Cited by 32 publications

References 41 publications

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

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

The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

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