Hypocretin, narcolepsy

Zeitzer JM, Nishino S, Mignot E (2006) The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci 27 368-74... 

Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000 355 39-40. 

Hypocretin A wakefulness-promoting hypothalamic neuropeptide, a deficiency of which is involved in the pathophysiology of narcolepsy. 

Brown, R. E. (2003). Involvement of hypocretins/orexins in sleep disorders and narcolepsy. Drug News Perspect. 16, 75-9. 

Peyron, C., Faraco, J., Rogers, W. et al. (2000). A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991-7. 

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, may be caused by the lack of hypocretin mRNA and peptides in humans (Peyron et al., 2000) or a disruption of the hypocretin receptor 2 or its ligand in dogs and mice (Lin et al., 1999 Chemelli et al., 1999). Hypocretin-containing neurons are located exclusively in the dorsomedial, lateral, and perifornical hypothalamic areas (Peyron et al., 1998). Two hypocretin sequences, Hcrt-1 (orexin-A) and Hcrt-2 (orexin-B), are generated from a single preprohypocretin (De Lecea et al., 1998 Peyron et al, 1998 Sakurai et al, 1998). Axons from these neurons are found in the hypothalamus, locus coeruleus (LC), raphe nuclei, tuberomamillary nucleus, midline thalamus, all levels of spinal cord, sympathetic and parasympathetic centers, and many other brain regions... 

Other activators of the histaminergic system may also be involved in wakefulness. The orexin (i.e. hypocretin) A and B neuropeptides were isolated from rat hypothalamic extracts. A mutation in the orexin-2 receptor gene was found to be associated with canine narcolepsy, and mice lacking the orexin peptide display increases in REM and NREM sleep and a decrease in wakefulness time during the active period of normal rodents. However, the exact role of orexin in physiological sleep and the mechanisms involved have not yet been elucidated. 

Hungs, M. Mignot, E. (2001). Hypocretin/orexin, sleep and narcolepsy. Bioessays 23, 397-408. 

Mieda, M. Yanagisawa, M. (2006). Rodent models of narcolepsy-cataplexy. In The Orexin/Hypocretin System Physiology and Pathophysiology, ed. S. Nishino T. Sakurai, Totowa, NJ Humana Press, pp. 255-66. 

Thannickal T. C., Moore R. Y., Nienhuis R. et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469-74. 

The hypocretin/orexin neurotransmitter system may play a central role in narcolepsy. An autoimmune process may cause destruction of hypocretin-producing cells. 

The main risk factor appears to be a genetic susceptibility to the illness. The majority of narcolepsy patients, particularly those with cataplexy, have a genetic marker known as HLA-DQB1 0602. Recent evidence indicates that the key dysfunction in narcolepsy is diminished activity of a newly discovered neurotransmitter known as hypocretin. This new evidence has led to the development of a new diagnostic test for narcolepsy and may ultimately lead to new treatments that act directly on hypocretin systems in the brain. 

Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci 2002 25 283-313. 

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