Acylated and unacylated ghrelin confer neuroprotection to mesencephalic neurons

Autor: Anne Grünewald, Wolfgang H. Oertel, Patrick P. Michel, Daniel Alvarez-Fischer, Marcus M. Unger, Vincent Ries, Johanna Wagner, Franca Vulinovic, Jens Carsten Möller, Christine Klein
Rok vydání: 2017
Předmět:
0301 basic medicine
medicine.medical_specialty
1-Methyl-4-phenylpyridinium
Tyrosine 3-Monooxygenase
medicine.drug_class
Acylation
Growth hormone secretagogue receptor
Motility
Biology
Neuroprotection
03 medical and health sciences
Nicardipine
0302 clinical medicine
Dopamine
Mesencephalon
Internal medicine
medicine
Animals
Enzyme Inhibitors
Rats
Wistar
Cells
Cultured
Neurons
Voltage-dependent calcium channel
Dose-Response Relationship
Drug
General Neuroscience
digestive
oral
and skin physiology
Receptor antagonist
Calcium Channel Blockers
Embryo
Mammalian
Nitro Compounds
Ghrelin
Rats
030104 developmental biology
Endocrinology
Mitochondrial respiratory chain
Neuroprotective Agents
Phosphopyruvate Hydratase
Propionates
Peptides
hormones
hormone substitutes
and hormone antagonists
030217 neurology & neurosurgery
medicine.drug
Zdroj: Neuroscience. 365
ISSN: 1873-7544
Popis: The polypeptide ghrelin is an endogenous ligand at the growth hormone secretagogue receptor 1a. To ghrelin multiple functions have been ascribed including promotion of gastrointestinal motility. Postprandial ghrelin levels have been reported to be reduced in patients suffering from Parkinson disease (PD). Experimental studies revealed neuroprotective effects of ghrelin in different PD models. The purpose of the present study was (i) to further elucidate the mechanism underlying the neuroprotective action of ghrelin and (ii) to determine whether these effects occur with both the acylated and the unacylated form. The study was conducted in primary mesencephalic cultures treated with mitochondrial complex I and complex II inhibitors. We show that protective effects of ghrelin against complex I inhibition with MPP+ were independent of the acylation status of ghrelin, although acylated ghrelin appeared to be more potent. Protection by both forms was also observed when neurons were exposed to the complex II inhibitor 3-NP. Both forms led to higher oxygen consumption rates upon electron transport chain uncoupling, indicating that the two peptides may exert uncoupling effects themselves. We demonstrate that the rescue provided by ghrelin required calcium influx through L-type voltage-gated calcium channels. Whereas the protective effects of acylated ghrelin required receptor binding, effects of the unacylated form remained unaffected by treatment with a ghrelin receptor antagonist. Importantly, inhibition of ghrelin O-acyltransferase failed to reduce the activity of unacylated ghrelin. Overall, our data suggest that both acylated and unacylated ghrelin afford protection to dopamine neurons but through mechanisms that only partially overlap.
Databáze: OpenAIRE
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