Study Title:

Ghrelin Function and Parkinson's

Study 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.

From press release:

Ghrelin, a hormone produced in the stomach, may be used to boost resistance to, or slow, the development of Parkinson's disease, Yale School of Medicine researchers report in a study published in a recent issue of the Journal of Neuroscience.

Parkinson's disease is caused by a degeneration of dopamine neurons in an area of the midbrain known as the substantia nigra, which is responsible for dopamine production. Reduced production of dopamine in late-stage Parkinson's causes symptoms such as severe difficulty in walking, restricted movements, delays in moving, lack of appetite, difficulty eating, periods of remaining motionless (known as "freezing") and head and limb tremors.

When the dopamine cells get sick and die, Parkinson's can develop. Yale researcher Tamas Horvath and colleagues found that ghrelin is protective of the dopamine neurons. "We also found that, in addition to its influence on appetite, ghrelin is responsible for direct activation of the brain's dopamine cells," said Horvath, chair and professor of comparative medicine and professor of neurobiology and obstetrics & gynecology at Yale School of Medicine. "Because this hormone originates from the stomach, it is circulating normally in the body, so it could easily be used to boost resistance to Parkinson's or it could be used to slow the development of the disease."

Horvath and colleagues conducted the study in mice that received ghrelin supplementation and in mice that were deficient in ghrelin hormone and in the ghrelin receptor. When compared to controls, mice with impaired ghrelin action in the brain had more loss of dopamine. Horvath said the results could be easily translated to human use because the ghrelin system is preserved through various species.

Ghrelin was previously associated with the release of growth hormones, appetite, learning, memory, and with the reward circuitry of the brain that regulates food cravings. Recent human studies show that body mass index, stored fat and diabetes are linked to Parkinson's disease. Past research also shows that obesity is a risk factor for neurodegeneration in mice.

In future work, Horvath and his team will try to determine ghrelin levels in both healthy individuals and Parkinson's patients. He will also determine whether altered ghrelin levels might be a biomarker of disease development and vulnerability.

The study was supported by the Michael J. Fox Foundation for Parkinson's Research.

Study Information

Zane B. Andrews, Derek Erion, Rudolph Beiler, Zhong-Wu Liu, Alfonso Abizaid, Jeffrey Zigman, John D. Elsworth, Joseph M. Savitt, Richard DiMarchi, Matthias Tschöp, Robert H. Roth, Xiao-Bing Gao, and Tamas L. Horvath
Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism
The Journal of Neuroscience
2009 November
Yale University School of Medicine, New Haven, Connecticut 06520.

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