The anti-apoptotic effect of orexin on pancreatic beta-cells, increase in peripheral insulin sensitivity, and reduced lipolysis in the adipose tissue, together confer an increased risk for obesity and type 2 DM (T2DM) in NA patients.
Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus.
Although today a reliable pathogenic hypothesis identifies the cause of NT1 as an autoimmune process destroying hypocretin-producing cells, there is no cure for narcolepsy, and the symptomatic pharmacological available treatments are not entirely effective for all symptoms.
This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.
Orexin receptor antagonists are clinically useful for treating insomnia, but thorough blockade of orexin signaling could cause narcolepsy-like symptoms.
Our analysis of in vivo expansion of HCRT-reactive TRAJ24<sup>+</sup> cells opens an avenue for further investigation of the autoimmune contribution to narcolepsy development.
These results indicate that it is unlikely that cross-reactivity between H1N1 hemagglutinin and hypocretin peptides presented by HLA-DQ6 is involved in the development of narcolepsy.
Thus, future neuroimaging studies should employ multimodal imaging methods in a large sample size of patients with narcolepsy and consider age, duration of disease, age at onset, severity, human leukocyte antigen type, cerebrospinal fluid hypocretin levels, and medication intake in order to elucidate possible neuroimaging characteristic of narcolepsy and identify therapeutic targets.
Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons.
As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy.
Two different types of association were identified: (1) Symptomatic type (5 pts): MS preceding the onset of narcolepsy, which was always without cataplexy (NwC); sleep onset REM episodes (SOREM) and hypocretin deficiency were observed in some, and lesions in the hypothalamus in all patients.
Although narcolepsy is predominantly associated with loss of hypocretin (orexin), the role of genetics is poorly understood and, therefore, is complementary to the diagnosis but not confirmatory.
Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.
The orexin-A and its receptors are associated with many physiological processes in peripheral organs and the central nervous system and play important roles in a series of human diseases, including narcolepsy, obesity, and drug addiction.
Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models.