Des-acyl ghrelin attenuates pilocarpine-induced limbic seizures via the ghrelin receptor and not the orexin pathway

Portelli, Jeanelle; Coppens, Jessica; Demuyser, Thomas; Smolders, Ilse Julia

doi:10.1016/j.npep.2015.04.004

Cited by 18 publications

(14 citation statements)

References 39 publications

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“…Biagini et al investigated that des-acylated ghrelin presented a trend in the prevention of pilocarpine-induced status epilepticus models [ 54 ]. Consistent with that, Portelli J found that des-acyl ghrelin can significantly elevated seizure thresholds and this action need ghrelin receptor to be involved [ 52 ]. Clinical studies tested des-acyl ghrelin levels in sersum and found that levels of acylated and des-acylated were in direct proportion to disease duration.…”

Section: Introductionsupporting

confidence: 55%

“…Des-acyl ghrelin was found to significantly elevate seizure thresholds in C57Bl/6 and wild type mice but not in ghrelin receptor knockout mice. It also has been found that des-acyl ghrelin exert anticonvulsant effect via ghrelin receptor rather not orexin pathway [ 52 ]. At present, there's still lack in studies investigating deep cellular and molecular mechanisms of ghrelin's antiepileptic effect.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical evidence of ghrelin as a therapeutic target in epilepsy

Yang

Fan

et al. 2017

Oncotarget

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Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, plays a major role in inhibiting seizures. However, the underlying mechanism of ghrelin's anticonvulsant action is still unclear. Nowadays, there are considerable evidences showing that ghrelin is implicated in various neurophysiological processes, including learning and memory, neuroprotection, neurogenesis, and inflammatory effects. In this review, we will summarize the effects of ghrelin on epilepsy. It may provide a comprehensive picture of the role of ghrelin in epilepsy.

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Section: Introductionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Preclinical evidence of ghrelin as a therapeutic target in epilepsy

Yang

Fan

et al. 2017

Oncotarget

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“…In another study using GHSR KO mice, des‐acyl ghrelin increased the pilocarpine‐evoked seizure threshold, thus acting as an anticonvulsant, in WT but not KO mice (Portelli et al . ). In a study examining the role of each isoform during myocardial injury, there was a protective therapeutic action of acylated ghrelin that was significantly weaker than des‐acyl ghrelin (Li et al .…”

Section: Discussionmentioning

confidence: 97%

Acylated but not des‐acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease

Bayliss

Lemus

Santos

et al. 2016

Journal of Neurochemistry

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The gut hormone ghrelin is widely beneficial in many disease states. However, ghrelin exists in two distinctive isoforms, each with its own metabolic profile. In Parkinson's Disease (PD) acylated ghrelin administration is neuroprotective, however, the role of des-acylated ghrelin remains unknown. In this study, we wanted to identify the relative contribution each isoform plays using the MPTP model of PD. Chronic administration of acylated ghrelin in mice lacking both isoforms of ghrelin (Ghrelin KO) attenuated the MPTP-induced loss on tyrosine hydroxylase (TH) neuronal number and volume and TH protein expression in the nigrostriatal pathway. Moreover, acylated ghrelin reduced the increase in glial fibrillary acidic protein and Ionized calcium binding adaptor molecule 1 microglia in the substantia nigra. However, injection of acylated ghrelin also elevated plasma des-acylated ghrelin, indicating in vivo deacetylation. Next, we chronically administered des-acylated ghrelin to Ghrelin KO mice and observed no neuroprotective effects in terms of TH cell number, TH protein expression, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 cell number. The lack of a protective effect was mirrored in ghrelin-O-acyltransferase KO mice, which lack the ability to acylate ghrelin and consequently these mice have chronically increased plasma des-acyl ghrelin. Plasma corticosterone was elevated in ghrelin-O-acyltransferase KO mice and with des-acylated ghrelin administration. Overall, our studies suggest that acylated ghrelin is the isoform responsible for in vivo neuroprotection and that pharmacological approaches preventing plasma conversion from acyl ghrelin to des-acyl ghrelin may have clinical efficacy to help slow or prevent the debilitating effects of PD.

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“…It is however uncertain to which receptor des-acyl ghrelin binds. Some studies show that des-acyl ghrelin is able to interact with the ghrelin receptor [19,20], while other studies suggest that des-acyl ghrelin interacts with another unknown receptor [56,57]. If des-acyl ghrelin would interact with a different receptor from acylated ghrelin, it is possible that increased des-acyl ghrelin is able to induce neuroprotection, even in ghrelin receptor KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…It is mainly produced by the X/A like cells of the stomach, where it is acylated at the third amino acid residue (serine) by ghrelin- O -acyltransferase (GOAT). This acylation step has long been considered necessary for its binding to the ghrelin receptor, although some recent studies show that des-acyl ghrelin, which lacks the acyl group, can function via the ghrelin receptor [19,20]. In the brain, in situ hybridization showed that the ghrelin receptor is present in the pituitary gland, the arcuate nucleus, the hippocampus, the median and ventral raphe nuclei, and the midbrain, such as the SNc and the ventral tegmental area (VTA) [21,22].…”

Section: Introductionmentioning

confidence: 99%

Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

Coppens

Bentea

Bayliss

et al. 2017

IJMS

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Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.

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Des-acyl ghrelin attenuates pilocarpine-induced limbic seizures via the ghrelin receptor and not the orexin pathway

Cited by 18 publications

References 39 publications

Preclinical evidence of ghrelin as a therapeutic target in epilepsy

Preclinical evidence of ghrelin as a therapeutic target in epilepsy

Acylated but not des‐acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease

Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

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