Disease relevance of HCRT

• The number of hypothalamic hypocretin (orexin) neurons is not affected in Prader-Willi syndrome [1].
• The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT) [2].
• Emphysema in heavy smokers with normal chest radiography. Detection and quantification by HCRT [3].
• HCRT may provide an alternative palliation for patients with advanced carcinoma showing obstructive jaundice [4].
• The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the Hcrt cell loss in narcolepsy [5].

Psychiatry related information on HCRT

• A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains [6].
• Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system [7].
• In addition to excessive daytime sleepiness, Prader-Willi syndrome (PWS) patients may show narcolepsy-like symptoms, such as sleep-onset rapid eye movement sleep and cataplexy, independent of obesity-related sleep disturbances, which suggests a disorder of the hypocretin neurons [1].
• Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in-depth investigations [8].
• However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans [9].

High impact information on HCRT

• We have determined that canine narcolepsy is caused by disruption of the hypocretin (orexin) receptor 2 gene (Hcrtr2) [10].
• Hypocretin-containing neurons have widespread projections throughout the CNS with particularly dense excitatory projections to monoaminergic centers such as the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotoninergic raphe nucleus, and dopaminergic ventral tegmental area [11].
• The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders [12].
• Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders [13].
• Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin) precursor or Hcrt receptor genes [5].

Chemical compound and disease context of HCRT

• Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy [14].
• Metabolic mechanism of wakefulness (and hunger) and sleep (and satiety): role of adenosine triphosphate and hypocretin and other peptides [15].
• Modafinil may increase wakefulness through activation of noradrenergic and dopaminergic systems, possibly through interaction with the hypocretin/orexin system [16].
• Wakefulness is promoted by brainstem and hypothalamic neurons producing acetylcholine, norepinephrine, dopamine, serotonin, histamine, and orexin/hypocretin [17].
• Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy [18].

Biological context of HCRT

• METHODS: We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes [7].
• Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system [6].
• We deconvolved 24-h plasma profiles of ACTH and cortisol, and determined their circadian rhythm by cosinor analysis in seven hypocretin-deficient narcoleptic males and seven matched controls [19].
• RESULTS: There was no significant difference in the total number of hypocretin-containing neurons among the seven PWS patients (in whom sufficient hypothalamic material was available to quantify total cell number) and seven age-matched controls, either in adults or in infants [1].
• Interestingly, we found inter-individual differences in methylation levels in HTR2A and HCRT in the placenta and in some loci of HERV-K in the placenta and liver [20].

Anatomical context of HCRT

• Hypocretin-containing cells are located exclusively in the lateral hypothalamus, with widespread projections to the entire neuroaxis [21].
• Input from the suprachiasmatic nucleus to hypocretin-containing neurons may explain the occurrence of clock-dependent alertness [21].
• Hypocretin-stimulated [(35)S]GTP gamma S binding, may thus be a useful functional assay for hypocretin receptors in both cell lines and brain tissue homogenates [22].
• The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone [23].
• Further, HCRT efferents from the lateral hypothalamus innervate midbrain dopamine (DA) nuclei, and DA cell bodies express HCRT receptors [24].

Associations of HCRT with chemical compounds

• Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs [14].
• These behavioral changes were negatively correlated with the loss of Hcrt-containing neurons but not with the loss of adenosine deaminase-immunoreactive neurons [25].
• Several groups of neurons have been shown to be inhibited by this action--including neurons containing histamine, norepinephrine, serotonin, hypocretin, and glutamate--and this inhibition promotes sleep [26].
• Although modafinil exhibits a small degree of dopaminergic action by blocking the dopamine transporter, the major effect of modafinil may be attributable to neuronal activity in the hypothalamus, particularly pertaining to the recently discovered peptides hypocretin 1 and 2 (also known as orexin A and B) [27].
• Modafinil has a novel mechanism and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate [28].

Regulatory relationships of HCRT

• This study aimed to identify G protein subtypes activated by hypocretin in rat pontine reticular nucleus oral part (PnO) and the hypocretin receptor subtype modulating acetylcholine (ACh) release in the PnO [29].
• Orexin-stimulated HIF-1 activity is due to both increased HIF-1alpha gene transcription and a down-regulation of von Hippel-Lindau (VHL), the E3 ubiquitin ligase that mediates the turnover of HIF-1 via the ubiquitin-proteasome pathway [30].

Other interactions of HCRT

• Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy [31].
• As studied with calcium digital imaging with fura-2, hypocretin raises cytoplasmic calcium via a mechanism based on G-protein enhancement of calcium influx through plasma membrane channels [32].
• The association of narcolepsy with a deficiency in a specific neurotransmitter, in this case, hypocretin, is reminiscent of the associations between Parkinson disease and dopamine, or early Alzheimer disease and acetylcholine [33].
• Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH) [34].
• These findings suggest that the hypothalamic hypocretin (orexin) system may be crucial to maintaining the arousal level and that lesions in the system can cause hypersomnia in MS [35].

Analytical, diagnostic and therapeutic context of HCRT

• DESIGN: We estimated the number of hypocretin neurons in postmortem hypothalami using immunocytochemistry and an image analysis system [1].
• Electrical stimulation of hypothalamic microslices that contained hypocretin cells and their axons evoked dynorphin release [36].
• High-resolution CT (HCRT) is extremely helpful in understanding pathomorphological changes, mode of spread of the disease, and sequential morphological change after antituberculous chemotherapy, and possibly in diagnosing activity of the disease [37].
• In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the Hcrt system [5].
• We provide evidence for the role of endogenously produced hypocretin/orexin in the physiological response to immobilization stress and identify the receptor subtype responsible for this action of the peptide [38].

References