Researchers from Paris may have found a new way to prevent neuron death in Parkinson disease (PD), by using the sleep-promoting protein orexin B.
Orexins A and B, small neuropeptides also known as hypocretin 1 and 2, are produced by the hypothamalus and come from a common precursor, prepro-orexin. The orexin system controls feeding, reward responses, and sleep. Lack of orexin results in narcolepsy. Sleep disorders frequently present in PD include sleep apnea syndrome, restless legs syndrome, and rapid eye movement sleep behavior disorder (RBD).
The hypothalamic orexin neurons degenerate in PD, along with the well-known dopamine-producing neurons. For this reason, the researchers were interested in understanding the effects of orexins on a rat neuron cell culture model of PD.
Led by Serge Guerreiro of Sorbonne Universités, the researchers used rat dopamine neurons taken from the midbrain and grown in culture.1 They tested whether orexins help these neurons survive. They found that orexin B substantially protected the neurons from the normal death that occurs when these cells mature in culture. Orexin A did not have this effect. The effect appeared to be a result of the action of orexin B on the OX2 subtype of neuronal receptor, but not the OX1 receptor subtype. Nicotine further improved cell survival when applied with orexin B but had no effect on survival on its own.
The scientists concluded, “Present data show that the hypothalamic peptide [orexin B] protects vulnerable midbrain [dopamine] neurons from degeneration and preserves their function while the homologous peptide [orexin A] has only limited effects.”
Loss of orexin cells could make the dopamine cell death even worse in PD. According to the study authors, “Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that is occurring in Parkinson disease might confer an increased vulnerability to midbrain DA neurons in this disorder.”
Orexin B could provide a new target for potential treatments of PD, alone or with other therapies. However, more studies, specifically in humans, would be needed.
The symptoms found in PD, narcolepsy and a related disorder, rapid eye RBD, seem to overlap. RBD can even be predictive of later development of PD. This provides further indirect evidence that the orexin B system may play a larger role than previously understood in mediating the symptoms of PD.
The article appeared in the December 31, 2014 issue of Molecular Pharmacology.
• The sleep-promoting protein orexin B, but not orexin A, protects dopamine cells in culture.
• Orexin B protection is further potentiated by nicotine.
• Orexin B may provide a new possible treatment for PD, but much more work is needed.
1. Guerreiro S, Florence C, Rousseau E, et al. The sleep modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine. Mol Pharmacol. 2014. pii: mol.114.095703. [Epub ahead of print]