Hypocretins / Orexins are neuropeptide with mutiple pharmacological effects
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Hypocretins/Orexin in Narcolepsy [1,2,3]
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Using Phoenix Pharmaceuticals' Hypocretin-1 / Orexin A RIA kit, Nishino, et al. have found that Hypocretin/Orexin-like immunoreactivity in the cerebrospinal fuid (CSF) from narcolepsy patients is under detectable levels [1] as compared with normal subjects (<40 ng/ml vs 285 ng/ml).

The hypothalamus is a major regulatory center for autonomic and endocrine homeostasis, were hypothalamic-specific peptides exert their important roles by transport to the pituitary, by entering the general circulation, or by secrection within the central nervous system. Hypocretins/Orexins are hypothalamic- specific peptides with neuro-excitatory, feeding behavior, endocrine and cardiovascular function [4,7,8,9,10,11]. Recently, attention has been focused on their role in sleep regulation [1,2,3,5,6]. Human narcolelpsy may relate to Hypocretin / Orexin deficiency in brain.

Neurons containing hypocretin are located exclusively in the lateral hypothalamus and send axons to mumerous regions throughout the central nervous system, including the major muclei implicated in sleep control. It was reported that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of Orexin A increased cell firing of intrinsic noradrenergic neurons. Orexin A increased arousal and locomotor activity and modulated neuroendocrine functions[5]. These data suggest that Hypocretins/Orexins play an important role in orchestrating the sleep-wake cycle.

Narcolepsy is a disabling sleep disorder affecting humans and animals. It is characterized by daytime sleepiness, cataplexy, and striking trasitions from wakefulness into rapid eye movement (REM) sleep [2]. Lin, et al. have found that canine narcolepsy can be caused by disruption of the Hypocretin/Orexin receptor 2 gene (Hcrtr2)[2]. Hornozygous Hypocretin knock out mice showed a phenotype strikingly similar to that in human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy [3].

This is the first report that Hypocretin neurotransmission is deficient in some people with narcolepsy. These results, together with the observation that hypocretin receptor and peptide gene alterations induce narcolepsy in animal models, suggest that Hypocretin/Orexin deficiency contributes to narcolepsy.

  1. Nishino, S. et al. Hypocretin (Orexin) deficiency in human narcolepsy. Lancet, 355, 39-40 (2000)
  2. Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98, 365-376 (1999)
  3. Chemelli, R.M., et al/ Narcolepsy in Orexin knock out mice: molecular genetics of sleep regulation. Cell 98, 437-451 (1999)
  4. De Lecea, L. et al. The Hypocretins hypothalamous-specific peptides with neuroexcitatory activity. Proc. Nat. Acad. Sci. 95, 322-327 (1998)
  5. Hagan, J.J. et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc. Nat. Acad. Sci. 96, 10911-10916 (1999)
  6. Siegel, J.M. Narcolepsy, a key role for Hypocretins (Orexins). Cell 98, 409-412 (1999)
  7. Samson, W.K., Gosnell, B., Chang, J.K., et al. Cardiovascular regulatory actions of the Hypocretins in brain. Brain Res. 831, 241-253 (1999)
  8. Kirchgessner, A.L. and Liu, M. Orexin synthesis and response in the gut. Neuron 1999 Dec. 24 (4): 941-51
  9. Lopez, M. et al. Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology 140, 5991-4 (1999)
  10. Yamamoto, Y. et al. Orexin receptors are expressed in the adreanal medulla of the rat. Brain Res Mol Brain Res. 65, 14-22 (1999)
  11. Antonarakis, S.E. and Mckusick V.A. OMIM *602393 Hypocretin Receptor
    12. Second Department of Internal Medicine, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Miyagi, Japan. Orexin-A-like immunoreactivity was detected in every region of human brain, but not in the pituitary. The highest concentration of orexin-A-like immunoreactivity in the human brain was found in hypothalamus (17.8 +/- 4.3 pmol/g wet weight, mean +/- SEM, n = 7), followed by thalamus, medulla oblongata, and pons. Orexin-A-like immunoreactivity was detected in the tumor tissues of ganglioneuroblastoma and neuroblastoma, but not in the tumor tissues of pheochromocytoma. Reverse phase high performance liquid chromatographic analyses of the orexin-A-like immunoreactivity in the human brain extracts and neuroblastoma extracts showed a single immunoreactive peak, which was eluted in an identical position to synthetic human orexin-A.

 

The Hypocretin/Orexin Story, Willis K. Samson and Zachary T. Resch.  TEM 11(7):257-262 (2000)