Seiji Nishino

..However, little is known about molecular alterations downstream of the hypocretin signals...

..In humans and mice a comparable pigmentation phenotype without any documented hair loss is caused by mutations within the melanophilin gene (MLPH)...

..It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy...

..Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy...

..As a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress...

..To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1...

..The commercial challenge to armodafinil may come from generic modafinil, which may become available in 2012, as well as from classical amphetamine and amphetamine-like compounds (for the treatment of narcolepsy)...

..Hypocretin replacement is also likely to be a new therapeutic option for hypocretin-deficient narcolepsy, but is still not available in humans. In this review, the pharmacologic and pathophysiologic aspects of narcolepsy are discussed...

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..In this review, the clinical, pathophysiological and pharmacological aspects of narcolepsy are discussed...

..Hypocretin-1 levels were moderately reduced in an additional 11 GBS, 5 Miller-Fisher syndrome, and 1 CIDP subject. Low levels in GBS occurred early in the disease and were associated with upper CNS level abnormalities...

..Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed...

..Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system...

..Over 90% of diagnosed narcoleptic patients are currently prescribed medications to control their symptoms; however, available treatments are merely symptomatic...

..In this chapter, the role of the hypothalamus in vigilance control is discussed, with a particular emphasis on the hypocretins/orexin system...

..Narcolepsy is therefore, an important model to study the link between sleep regulation and other fundamental hypothalamic functions...

..This investigation illustrates the need for coordinated study of multiple phenotypes in mouse models with altered sleep/wake patterns...

..Our definition of DREM in murine narcolepsy may provide good electrophysiological measures for cataplexy-equivalent episodes...

..Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine...

..To determine if hypocretin deficiency is associated with abnormally low serum leptin levels, a putative cause of increased body mass index in narcoleptics...

..The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans...

..To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy...

..Currently, hypocretin replacement therapy has emerged as a promising therapeutic option, and experiments using gene therapy and cell transplantation are in progress...

..Several methods have been developed to assess EDS, although each of them has limitations. Treatment is available for the great majority of cases...

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..These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations...

..Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels...

..To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1...

..Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data...

..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...

..Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system...

..No correlation was found between CSF hypocretin-1 and corticosterone. CONCLUSIONS: Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons...

..Hypocretin-deficient human narcolepsy appears to be a more complex condition than a simple sleep disorder, and it may serve as an important disease model for studying hypothalamic function in health and disease...

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..This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds...

..However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved...

..e., autoreceptors) for the regulation of cataplexy. Because the A11 cell group projects to the spinal ventral horn, the A11 D(2/3) receptive mechanisms may directly modulate the activity of spinal motoneurons and modulate cataplexy...

..Difference in the kinetics of hypocretins should be considered for interpreting ICV effects of hypocretins...

..Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted...

..Hypocretin receptor agonists are likely to be ideal therapeutic options for hypocretin-deficient narcolepsy but such compounds are still not available in humans...

..Similarly, the pathophysiology of idiopathic hypersomnia, another defined primary hypersomnia, is largely unknown. This chapter discusses our current understanding of the neurochemistry of EDS, a disease of awakening...

..Our canines may therefore be an invaluable resource in PLMS research...

..The presence of hypocretin peptides in Hcrtr 2-mutated animals suggests that neurotransmission through Hcrtr 1 may be intact, arguing for a preferential importance of Hcrtr 2-mediated function in narcolepsy...

..These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome...

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..Involvement of abnormal inactivation of bilateral pathways to the spinal motoneurones due to a deficiency in hypocretin neurotransmission is suggested in the occurrence of cataplexy...

..We also report on novel strategies designed to compensate for hypocretin deficiency and on the use of immunosupression at the time of narcolepsy onset...

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..The effects of muscimol indicate that the stimulation of cataplexy might be elicited by local neuronal inhibition...

..These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders...

..Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil...

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..This result identifies hypocretins as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients...

..Our results also suggest that presynaptic activation of DA transmission is a key pharmacological property mediating the wake-promoting effects of currently available CNS stimulants...

..These results indicate an important link between circadian control of sleep and energy homeostasis via the hypocretin system...

..Cataplexy and a dysfunction in the maintenance of vigilance states, but not abnormal REM sleep generation, may therefore be central to narcolepsy...

..In this review, we will introduce recently obtained knowledge of the pharmacokinetics of hypnosedatives and CNS stimulants and their applications for patients affected with insomnia and EDS...

..These results do not favor the hypothesis of a role for CRF or PGs in the pathophysiology of sleep disturbances in schizophrenia...

..Ambulatory activity monitoring may be a useful non-invasive method for future pharmacological and development studies in the narcoleptic canine model...

..This review summarizes a Mini-Symposium presented at the 2006 Annual Meeting of the Society for Neuroscience...

..Our results also suggest that the anticataplectic effect of "selective" serotonergic uptake inhibitors in human narcolepsy might be mediated by their less selective active metabolites...

..Future research in this area is needed to establish functional significance...

..Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons...

..In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations...

..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...

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..Finally, in view of the tremendous advances that have occurred in the past few years in our understanding of the pathophysiology of canine and human narcolepsy, we also highlight these discoveries...

..This chapter starts with an overview of the clinical aspects of narcolepsy, followed by an update on the pathophysiology. Finally, we discuss the expectations from future narcolepsy research...

..The present findings suggest that orexins have an antinociceptive role in at least four different types of pains, probably acting on both the brain and spinal cord...

..The results of the present study indicate that some patients with GBS have lower levels of CSF hypocretin-1...

..In this study, we measured CSF hypocretin-1 levels in various age ranges from infants to elder people to investigate the age-dependent change of hypocretin concentrations...

..Low CSF hypocretin-1 is therefore very specific for HLA DR2 positive narcolepsy-cataplexy, and the deficiency is likely to be established at the early stage of the disease...

..Very few studies have evaluated narcolepsy in Asian countries, outside of Japan. Our goal was to study narcolepsy at the genetic, clinical and pathophysiological level in Korea...

..The extent of sleep disruption in this case of organic insomnia was similar to cases of familial fatal insomnia, but was at least partially reversible with treatment...

..3 pg/ml vs. 65.2+/-21.2 pg/ml; p=0.03.) These data indicate that orexin-A/hypocretin-1 may therefore play an important role in the various physiological responses including sleep, feeding, and the overall metabolism in ICH patients...

..A more global hypothalamic lesion demonstrated by brain magnetic resonance imaging (MRI) after surgery seemed to cause marked disinhibition of REM sleep as well as hypersomnolence in this patient...

..Thus, the blocking of the histamine H1 or H2 receptor may produce antinociception and enhance the orexin A-induced antinociception...

..In young rats and monkeys, levels of HCRT-1 are highest at the end of the wake-active period and lowest toward the end of the sleep period. However, the effects of age on the diurnal rhythm of HCRT-1 are not known...

..Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders...

..Orexin-A levels vary moderately between subjects, but are quite consistent within the same subject. Thus, for the diagnostic evaluation of narcolepsy, the time of CSF collection should have little impact...

..MCH neurons are not likely to change their activities during this sleep-promoting process...

..The gait difficulties resolved with venlafaxine. This case demonstrates that status cataplecticus can be misdiagnosed as a psychogenic gait disorder...

..Most likely, this narcolepsy is a consequence of demyelination and dysfunction of hypocretin pathways, but direct injury to the hypocretin neurons may also occur...

..These results suggest that dynamics of orexin signaling observed may have functional roles for neuronal damage associated with transient ischemia...

..018 by Wilcoxon signed-rank test). These results suggest that subpopulations of the preoptic neurons give an inhibitory tone to the activities of the orexin neurons in the perifornical/lateral hypothalamic areas...

..In those narcoleptics where CSF levels are within the normal range, it is possible that not all of the HCRT neurons are lost and that the surviving HCRT neurons might be increasing output of CSF HCRT...

..Increased hypocretin tone during REM deprivation may be important in mediating some of the effects of REM sleep deprivation such as antidepressant effects, hyperphagia and increased sympathetic activity...

..The clinical borderland of narcolepsy and the diagnostic value of different markers of narcolepsy remain controversial and were assessed in a consecutive series of 27 patients with hypersomnia of (mainly) neurological origin...

..HLA typing and cerebrospinal fluid hypocretin levels were also evaluated in 4 patients. Niemann-Pick disease diagnosis was confirmed in all cases biochemically and by the presence of foam cells in the bone marrow...

..These functional data suggested that a sleep-generating element in the ventromedial part of the rostral basal forebrain provides an inhibitory influence on the activities of the orexin neurons in the tuberal part of the hypothalamus...

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..Decreased hypothalamic hypocretin neurotransmission may be involved in this symptomatic case of hypersomnia associated with acute disseminated encephalomyelitis...

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..As almost nothing is known on the pathophysiology of non- hypocretin deficient hypersomnias, we believe this work to be ideally suited for a small grant application. ..

..We believe that results from these studies will bring new insights regarding the roles of the hypocretin/histamine interaction in narcolepsy and other EDS disorders and better treatment modalities in humans. ..

..We believe that results from these studies will bring new insights regarding the roles of the hypocretin/histamine interaction in narcolepsy and other EDS disorders and better treatment modalities in humans. ..