Importance of hypocretins in the pathology of narcolepsy
Keywords:
NARCOLEPSY, CATAPLEXY, NEUROPEPTIDES, SLEEP, VIGIL, REM SLEEP, HYPOTHALAMUSAbstract
Hypocretins 1 and 2 are peptidic neuromodulator found in neurons located in the hypothalamus. These neurons carry information to diverse areas of the central nervous system. Recently, it has been discovered that the alteration of the hypocretin system is related to the pathology of narcolepsy. This brief review intends to show the association between hypocretins and narcolepsy, and the role of hypocretins in the regulation of the sleep-wakefulness cycle.
References
1) Aldrich MS. Narcolepsy. N Engl J Med 1990; 323(6): 389-94.
2) Aldrich MS. Narcolepsy. Neurology 1992; 42(7 Suppl 6): 34-43.
3) Aldrich MS. Diagnostic aspects of narcolepsy. Neurology 1998; 50(2 Suppl 1): S2-7.
4) Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin 1996; 14(3): 545-71.
5) Guilleminault C, Anagnos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC (eds.), Principles and practices of sleep medicine. Philadelphia: Saunders, 2000: 676-86.
6) Guilleminault C, Heinzer R, Mignot E, Black J. Investigations into the neurologic basis of narcolepsy. Neurology 1998; 50(2 Suppl 1): S8-15.
7) Mignot E. A hundred years of narcolepsy research. Archives Italiennes de Biologie 2001; 139(3): 207-20.
8) Siegel JM. Narcolepsy: a key role for hypocretins (orexins). Cell 1999; 98: 409-12.
9) de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95(1): 322-7.
10) Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573-85.
11) Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18: 9996-10015.
12) Hungs M, Mignot E. Hypocretin/orexin, sleep and narcolepsy. Bioessays 2001; 23(5): 397-408.
13) de Lecea L, Sutcliffe JG. The hypocretins/orexins: novel hypothalamic neuropeptides involved in different physiological systems. Cell Mol Life Sci 1999; 56(5-6): 473-80.
14) Mignot E. A commentary on the neurobiology of the hypocretin/orexin system. Neuropsychopharmacology 2001; 25(5 Suppl): S5-S13.
15) Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 2001; 24: 429-58.
16) Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 2000; 23(8): 359-65.
17) Martin G, Fabre V, Siggins GR, de Lecea L. Interaction of the hypocretins with neurotransmitter in the nucleus accumbens. Regul Pept 2002; 104(1-3): 111-7.
18) Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98(3): 365-76.
19) Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98(4): 437-51.
20) Gerashchenko D, Kohls MD, Greco M, Waleh NS, Salin-Pascual R, Kilduff TS, et al. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci 2001; 21(18): 7273-83.
21) Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355(9197): 39-40.
22) Kanbayashi T, Inoue Y, Chiba S, Aizawa R, Saito Y, Tsukamoto H, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002; 11(1): 91-3.
23) Tsukamoto H, Ishikawa T, Fujii Y, Fukumizu M, Sugai K, Kanbayashi T. Undetectable Levels of CSF Hypocretin-1 (Orexin-A) in Two Prepubertal Boys with Narcolepsy. Neuropediatrics 2002; 33: 51-2.
24) Kanbayashi T, Yano T, Ishiguro H, Kawanishi K, Chiba S, Aizawa R, et al. Hipocretin-1 (orexin-A)levels in human lumbar CSF in different age groups: infant to elderly persons. Sleep 2002; 25(3): 337-9.
25) Ripley B, Overeem S, Fujiki N, Nevsimalova S, Uchino M, Yesavage J, et al. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57: 2253-8.
26) Bassetti CL, Gugger M, Mathis J, Sturzenegger C, Radanov B, Ripley B, et al. Cerebrospinal fluid levels of hypocretin (orexin) in hypersomnolent patients without cataplexy. Actas Fisiol 2001; 7: 205.
27) Overeem S, van Hilten JJ, Ripley B, Mignot E, Nishino S, Lammers GJ. Normal hypocretin-1 levels in Parkinson's disease patients with excessive daytime sleepiness. Neurology 2002; 58: 498-9.
28) Higuchi S, Usui A, Murasaki M, Matsushita S, Nishioka N, Yoshino A, et al. Plasma orexin-A is lower in patients with narcolepsy. Neurosci Lett 2002; 318(2): 61-4.
29) Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6: 991-7.
30) Mignot E, Tafti M, Dement WC, Grumet FC. Narcolepsy and immunity. Adv Neuroimmunol 1995; 5: 23-37.
31) Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469-74.
32) Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region. J Neuroimmunol 2001; 117(1-2): 9-20.
33) Dragunow M, Faull R. The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 1989; 29(3): 261-5.
34) Torterolo P, Yamuy J, Sampogna S, Morales F, Chase M. C-fos expression in hypocretinergic neurons during wakefulness and carbachol-induced active sleep. Sleep 2001; 24 (Suppl.): A155-6.
35) Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase M. Fos immunoreactivity in hypocretinergic neurons of the cat during active wakefulness, quiet wakefulness and quiet sleep. Actas Fisiol 2001; 7: 196.
36) Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase MH. Hypothalamic neurons that contain hypocretin (orexin) express c-fos during active wakefulness and carbachol-induced active sleep. Sleep Res Online 2001; 4: 25-32. http://www.sro.org/2001/Torterolo/25.
37) Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase MH. Hypocretinergic neurons are primarily involved in activation of the somatomotor system. Sleep 2003; 26(1): 25-8.
38) Kiyashchenko LI, Mileykovskiy BI, Maidment N, Siegel JM. Hypocretin1/Orexin-A release across the sleep-wakefulness cycle. Sleep 2002; 25: 393A.
39) Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M, et al. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 2000; 873(1): 181-7.
40) Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 2001; 98(17): 9965-70.
41) Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ. Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome. Neurology 2002; 59: 639-41.
42) Alam MN, Gong H, Alam T, Jaganath R, McGinty D, Szymusiak R. Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area. J Physiol 2002; 538(Pt 2): 619-31.
43) Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR, et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000; 20(20): 7760-5.
44) Xi MC, Morales FR, Chase MH. Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res 2001; 901: 259-64.
45) Yamuy J, Xi MC, Fung SJ, Torterolo P, Zhang J, Rojas MJ, et al. Effects of hypocretin (orexin) in pontine nuclei involved in active sleep. Actas Fisiol 2001; 7: 57.
46) Lin Y, Matsumura K, Tsuchihashi T, Abe I, Iida M. Chronic central infusion of orexin-A increases arterial pressure in rats. Brain Res Bull 2002; 57(5): 619-22.
47) Vanini G, Torterolo P, Falconi A, Velluti RA. The hypothalamic hypocretinergic system modulates auditory unit firing at the inferior colliculus. Sleep 2003 (en prensa).
48) Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J Pharmacol Exp Ther 1999; 289(1): 219-23.
49) John J, Wu M, Siegel JM. Systemic administration of hipocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000; 3(1): 23-8.
2) Aldrich MS. Narcolepsy. Neurology 1992; 42(7 Suppl 6): 34-43.
3) Aldrich MS. Diagnostic aspects of narcolepsy. Neurology 1998; 50(2 Suppl 1): S2-7.
4) Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin 1996; 14(3): 545-71.
5) Guilleminault C, Anagnos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC (eds.), Principles and practices of sleep medicine. Philadelphia: Saunders, 2000: 676-86.
6) Guilleminault C, Heinzer R, Mignot E, Black J. Investigations into the neurologic basis of narcolepsy. Neurology 1998; 50(2 Suppl 1): S8-15.
7) Mignot E. A hundred years of narcolepsy research. Archives Italiennes de Biologie 2001; 139(3): 207-20.
8) Siegel JM. Narcolepsy: a key role for hypocretins (orexins). Cell 1999; 98: 409-12.
9) de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95(1): 322-7.
10) Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573-85.
11) Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18: 9996-10015.
12) Hungs M, Mignot E. Hypocretin/orexin, sleep and narcolepsy. Bioessays 2001; 23(5): 397-408.
13) de Lecea L, Sutcliffe JG. The hypocretins/orexins: novel hypothalamic neuropeptides involved in different physiological systems. Cell Mol Life Sci 1999; 56(5-6): 473-80.
14) Mignot E. A commentary on the neurobiology of the hypocretin/orexin system. Neuropsychopharmacology 2001; 25(5 Suppl): S5-S13.
15) Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 2001; 24: 429-58.
16) Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 2000; 23(8): 359-65.
17) Martin G, Fabre V, Siggins GR, de Lecea L. Interaction of the hypocretins with neurotransmitter in the nucleus accumbens. Regul Pept 2002; 104(1-3): 111-7.
18) Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98(3): 365-76.
19) Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98(4): 437-51.
20) Gerashchenko D, Kohls MD, Greco M, Waleh NS, Salin-Pascual R, Kilduff TS, et al. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci 2001; 21(18): 7273-83.
21) Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355(9197): 39-40.
22) Kanbayashi T, Inoue Y, Chiba S, Aizawa R, Saito Y, Tsukamoto H, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002; 11(1): 91-3.
23) Tsukamoto H, Ishikawa T, Fujii Y, Fukumizu M, Sugai K, Kanbayashi T. Undetectable Levels of CSF Hypocretin-1 (Orexin-A) in Two Prepubertal Boys with Narcolepsy. Neuropediatrics 2002; 33: 51-2.
24) Kanbayashi T, Yano T, Ishiguro H, Kawanishi K, Chiba S, Aizawa R, et al. Hipocretin-1 (orexin-A)levels in human lumbar CSF in different age groups: infant to elderly persons. Sleep 2002; 25(3): 337-9.
25) Ripley B, Overeem S, Fujiki N, Nevsimalova S, Uchino M, Yesavage J, et al. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001; 57: 2253-8.
26) Bassetti CL, Gugger M, Mathis J, Sturzenegger C, Radanov B, Ripley B, et al. Cerebrospinal fluid levels of hypocretin (orexin) in hypersomnolent patients without cataplexy. Actas Fisiol 2001; 7: 205.
27) Overeem S, van Hilten JJ, Ripley B, Mignot E, Nishino S, Lammers GJ. Normal hypocretin-1 levels in Parkinson's disease patients with excessive daytime sleepiness. Neurology 2002; 58: 498-9.
28) Higuchi S, Usui A, Murasaki M, Matsushita S, Nishioka N, Yoshino A, et al. Plasma orexin-A is lower in patients with narcolepsy. Neurosci Lett 2002; 318(2): 61-4.
29) Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6: 991-7.
30) Mignot E, Tafti M, Dement WC, Grumet FC. Narcolepsy and immunity. Adv Neuroimmunol 1995; 5: 23-37.
31) Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469-74.
32) Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region. J Neuroimmunol 2001; 117(1-2): 9-20.
33) Dragunow M, Faull R. The use of c-fos as a metabolic marker in neuronal pathway tracing. J Neurosci Methods 1989; 29(3): 261-5.
34) Torterolo P, Yamuy J, Sampogna S, Morales F, Chase M. C-fos expression in hypocretinergic neurons during wakefulness and carbachol-induced active sleep. Sleep 2001; 24 (Suppl.): A155-6.
35) Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase M. Fos immunoreactivity in hypocretinergic neurons of the cat during active wakefulness, quiet wakefulness and quiet sleep. Actas Fisiol 2001; 7: 196.
36) Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase MH. Hypothalamic neurons that contain hypocretin (orexin) express c-fos during active wakefulness and carbachol-induced active sleep. Sleep Res Online 2001; 4: 25-32. http://www.sro.org/2001/Torterolo/25.
37) Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase MH. Hypocretinergic neurons are primarily involved in activation of the somatomotor system. Sleep 2003; 26(1): 25-8.
38) Kiyashchenko LI, Mileykovskiy BI, Maidment N, Siegel JM. Hypocretin1/Orexin-A release across the sleep-wakefulness cycle. Sleep 2002; 25: 393A.
39) Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M, et al. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 2000; 873(1): 181-7.
40) Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 2001; 98(17): 9965-70.
41) Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ. Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome. Neurology 2002; 59: 639-41.
42) Alam MN, Gong H, Alam T, Jaganath R, McGinty D, Szymusiak R. Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area. J Physiol 2002; 538(Pt 2): 619-31.
43) Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR, et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000; 20(20): 7760-5.
44) Xi MC, Morales FR, Chase MH. Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res 2001; 901: 259-64.
45) Yamuy J, Xi MC, Fung SJ, Torterolo P, Zhang J, Rojas MJ, et al. Effects of hypocretin (orexin) in pontine nuclei involved in active sleep. Actas Fisiol 2001; 7: 57.
46) Lin Y, Matsumura K, Tsuchihashi T, Abe I, Iida M. Chronic central infusion of orexin-A increases arterial pressure in rats. Brain Res Bull 2002; 57(5): 619-22.
47) Vanini G, Torterolo P, Falconi A, Velluti RA. The hypothalamic hypocretinergic system modulates auditory unit firing at the inferior colliculus. Sleep 2003 (en prensa).
48) Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J Pharmacol Exp Ther 1999; 289(1): 219-23.
49) John J, Wu M, Siegel JM. Systemic administration of hipocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000; 3(1): 23-8.
Downloads
Published
2003-05-30
How to Cite
1.
Torterolo P, Vanini G. Importance of hypocretins in the pathology of narcolepsy. Rev. Méd. Urug. [Internet]. 2003 May 30 [cited 2024 Oct. 18];19(1):27-33. Available from: https://revista.rmu.org.uy/index.php/rmu/article/view/953
Issue
Section
Review or Update and Updates
