Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism

Abstract

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.

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Unilateral microinjection of ghrelin causes the contralateral posturing and anticatalepsy effect, which is likely resulted from enhanced dopamine release induced by ghrelin directly and further activates the pathway of basal ganglia from the ipsilateral cortex. This was ARTICLE further confirmed by our in vitro and in vivo studies that intracerebroventricular injection of ghrelin in rats produces a dramatic enhancement of dopamine turnover rate and dopamine release in the striatum, which is in accordance with the studies that intraperitoneal administration of ghrelin improves the impairment of rota-rod performance in mouse MPTP-induced PD models 49 by stimulating dopamine overflow or dopamine turnover in the nucleus accumbens 9,12,50,51 . All together, our findings show that ghrelin, via specific blockage of KCNQ channel function, can increase the firing of mesencephalic dopaminergic neurons and mediate anticataleptic effects.…”

“…It is mainly secreted from stomach 7 , with small amounts produced in the brain 11 . GHS-R is expressed in various brain areas including SNc, hypothalamus, ventral tegmental area and hippocampus where ghrelin directly modulates the neuronal activity 9,10,12,13 . In SNc, ghrelin electrically activates dopaminergic neurons, and increases dopamine concentration in the striatum 12 .…”

Nutrient Selection in the Absence of Taste Receptor Signaling

“…In this regard, we envisage a particularly central role for the metabolism-controlling gut factor ghrelin (Tschöp et al, 2000) in modulating dopamine levels during situations associated with low blood glucose levels, including starvation. In fact, a recent study by Andrews et al (2009) has demonstrated that ghrelin promotes tyrosine hydroxylase gene expression in substantia nigra concomitantly to increasing dopamine concentration in striatum. In addition, Andrews et al (2009) have also shown that peripheral ghrelin contributes to the maintenance and protection of normal nigrostriatal dopamine function via UCP2-dependent mitochondrial mechanisms.…”

“…In fact, a recent study by Andrews et al (2009) has demonstrated that ghrelin promotes tyrosine hydroxylase gene expression in substantia nigra concomitantly to increasing dopamine concentration in striatum. In addition, Andrews et al (2009) have also shown that peripheral ghrelin contributes to the maintenance and protection of normal nigrostriatal dopamine function via UCP2-dependent mitochondrial mechanisms. More generally, the body of data produced by Horvath, Andrews, and colleagues (Andrews et al, 2008Horvath et al, 2009) indicates that, under conditions of excessively low blood glucose levels, increased ghrelin signaling may activate mitochondrial respiration and promote fatty acid oxidation in dopamine neurons as an alternative fuel source.…”

Effects of Long Acting Methylphenidate on Ghrelin Levels in Male Children with Attention Deficit Hyperactivity Disorder: An Open Label Trial

“…Ghrelin may also exert developmental and organizational effects during perinatal life like blastocyst development, perinatal growth and neurogenesis 14 . In addition, ghrelin has neuroprotective effects such as promoting and protecting nigrostriatal dopamine function via mitochondrial mechanisms 19 . Ghrelin has been associated with many psychiatric symptoms and psychiatric diseases as well as psychotropic drug effects and side effects 14,16,[20][21][22] .…”