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Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism.
J. Neurosci. 29, 14057-65 (2009)
Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
0.000
2.940
162
164
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Sprache
englisch
Veröffentlichungsjahr
2009
HGF-Berichtsjahr
0
ISSN (print) / ISBN
0270-6474
e-ISSN
1529-2401
Zeitschrift
Journal of Neuroscience
Quellenangaben
Band: 29,
Heft: 45,
Seiten: 14057-65
Verlag
Society for Neuroscience
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Diabetes and Obesity (IDO)
POF Topic(s)
30201 - Metabolic Health
Forschungsfeld(er)
Helmholtz Diabetes Center
PSP-Element(e)
G-502200-001
PubMed ID
19906954
WOS ID
000271664000001
Erfassungsdatum
2009-11-11