Orexin cell transplant reduces behavioral arrest severity in narcoleptic mice.

Narcolepsy is a sleep disorder that has been associated with the loss of orexinergic neurons from the lateral hypothalamic area. This loss leads to dysregulated sleep and cataplexy attacks. Therapeutic options are currently limited to symptom management with pharmacotherapy and nonpharmacological approaches. Nonetheless, cell replacement therapy could offer relief, and research in the field has yielded positive results for other neurodegenerative disorders, such as Parkinson's disease. Thus, we propose that orexin cell rich grafts could help improve narcoleptic symptoms in the orexin/ataxin-3 mouse model of narcolepsy. For this purpose, we isolated EGFP+ cells from either orexin/EGFP or CAG-EGFP mice with the use of a flow cytometer and grafted them into the pedunculopontine and laterodorsal tegmentum nuclei (PPT/LDDT) of orexin/ataxin-3 mice. Our results show that even small orexinergic grafts can reduce the severity of behavioral arrests, with a median reduction of 30.31% in episode duration, 51.35% for number of events and 69.73% in time spent in the behavioral arrest state and help with sleep fragmentation measured in number of bouts per behavioral state. Surprisingly, control grafts made from cerebellar tissue also reduced behavioral arrest severity, but to a lesser degree. Although still at a very early stage, these results show that there is potential in cell grafts for improving aspects of the narcoleptic phenotype and further research could help elucidate realistic expectations of an orexin cell replacement therapy for narcolepsy.

Understanding sleep-wake mechanisms and drug discovery.

INTRODUCTION: Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use. Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy. Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep medication.

Potential participation of cystatin C in rapid eye movement sleep (REMS) modulation.

It has been hypothesized that proteins modulate rapid eye movement sleep (REMS). Studies have shown an increase in the liberation of proteins in the mesencephalic reticular formation of cats during REMS. It has also been determined that protein-synthesis inhibitors diminish REMS and that protease-inhibitors increase this sleep phase. These and other studies support the importance of "di novo" protein molecules in sleep, and in particular, in REMS regulation. In this context, it is important to determine the role of endogenous proteases and their endogenous inhibitors in sleep regulation. In this study, we found that Cystatin C (CC), an endogenous protease inhibitor, diminishes wakefulness and increases REMS. We have also found an increase in CC expression after REMS deprivation and a tendency to decrease after a 2 h period of REMS rebound. We further showed that REMS deprivation increases the expression of Cathepsin H (CH), a protease inhibited by CC. These results suggest that naturally occurring protease-inhibitors enhance REMS, perhaps by facilitating the availability of proteins.

Cortistatin, a modulatory peptide of sleep and memory, induces analgesia in rats.

Cortistatin is a neuropeptide structurally related to somatostatin that induces sleep and interferes with the memory process. Very likely affecting other neurotransmission systems, such as: acetylcholine, gamma-aminobutyric acid, and noradrenaline. For example, cortistatin inhibits acetylcholine excitatory actions in the hippocampus. It is known that acetylcholine is involved in the regulation of several processes, such as pain, temperature, sleep, and memory. Since cortistatin seems to interact with acetylcholine, we decided to explore whether cortistatin participates in the system that modulates the noxious stimulus-evoked behavior. The intracerebroventricular administration of cortistatin increased the threshold to evoke a defensive behavior by a nociceptive stimulus. These observations suggest that cortistatin is part of the system that regulates pain perception.