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2005 Fiscal Year Final Research Report Summary

CSF histamine contents in narcolepsy and other sleep disorders.

Research Project

Project/Area Number 16614002
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 睡眠学
Research InstitutionAkita University

Principal Investigator

SHIMIZU Testuo  Akita University, School of Medicine, Professor, 医学部, 教授 (90170977)

Project Period (FY) 2004 – 2005
Keywordshistamine / orexin / hypocretin / narcolepsy / idiopathic hypersomnia / recurrent hypersomnia / obstructive sleep apnea syndrome
Research Abstract

Introduction : It was reported that histamine neurotransmission is decreased in hypocretin deficient narcoleptic subjects. Thus, impaired histaminergic neurotransmission may be an important pathophysiological mechanism in narcolepsy and other sleep disorders. In the current study, we have measured CSF histamine and hypocretin (orexin) content in patients with narcolepsy with and without cataplexy, idiopathic hypersomnia (IHS), recurrent hypersomnia (RH), obstructive sleep apnea syndrome (OSAS) and in the controls to examine whether histaminergic neurotransmissions are altered in these sleep disorders.
Methods : Fifty narcolepsy, 45 IHS, 18 OSAS and 69 neurological control subjects were included. Narcoleptic subjects include both with and without cataplexy. Thirty five narcolepsy were shown to have very low CSF hypocretin levels (mean+/-SEM: 43+/-1.8pg/ml), while hypocretin levels in 15 narcolepsy (242+1-11pg/ml) were in the same range of normal controls (289+/-11pg/ml), and thus defined … More as a non-deficient narcolepsy. CSF samples, collected between 9:00 am to 5:00 p.m., were frozen (-80C) immediately and kept until the measurements were done. Hypocretin-1 was measured in the unextracted CSF samples using commercially available radioimmunoassay kits (Phoenix Pharmaceuticals, Belmont, CA), as previously reported. Histamine concentrations in the CSF were detected by a HPLC(ECD-300, Eicom, Kyoto)-fluorescence spectromonitor (L7485, Hitachi ; Ex:355, Em:450 nm) system ; The CSF samples were separated in a reversed-phase separation column (SC-5ODS, Eicom) using mobile phase of 5 % methanol in 0.16 M KH2PO4 containing 0.8 mM sodium octanesulfonate (pH 4.5) at a flow rate 0.3 ml/ min. Then eluate was subjected to the postcolumn derivatization with mixture of 2.5 M NaOH (0.06 ml/min) and 0.05 % OPA (0.06 ml/min) in a reaction coil (5 m x 0.25 mm I.D.) at 42 degree C, then added 2 M H3PO4(0.13 ml/min) to stop the reaction. The concentrations of histamine were quantified with a PowerChrom (AD Instruments, Australia), using pure histamine standards (Sigma). The detection limit was 10 pg (50 fmol). The hypocretin levels of other sleep disorders (IHS: 240+/-14 pg/ml, OSAS: 265+/-26 pg/ml) were as same as those with neurological controls (289+/-11 pg/ml). Histamine measurements were done with a fluorometric HPLC. All measurement was done blindly, and each CSF sample was measured twice, and the mean values of two measurements are reported. For statistical analysis, ANOVA with Donferroni/Dunn were used. The statistical significance was set to <0.003.
Results : We found significantly lower histamine levels in narcoleptic subjects with hypocretin-deficient (197+/-40pg/ml, p=0.0001), without hypocretin-deficient (193+/-57pg/ml, p=0.002) and IHS (144+/-35pg/ml, p=0.0002) compered to neurological controls (409+/-31pg/ml). Histamine levels in patients with OSAS (382+/-59pg/ml, p=0.66) were as same as those in neurological controls. CSF histamine values were not significantly correlated with hypocretin levels and gender, age and status of the medication.
Conclusions : Similar to findings obtained by Nishino et al., histamine neurotransmission is decreased in hypocretin deficient narcoleptic subjects. In addition, we found that the histamine levels in the patients with narcolepsy without hypocretin-deficient and IHS were also significantly decreased. In the previous report, histamine levels in narcolepsy without hypocretin-deficient were relatively low but did not reach statistical significance levels. The discrepancy of these results should be further studied. However our results indicated that the hypersomnia expressed by the patients with narcolepsy and IHS are explained by the low histamine levels. On the other hand, the hypersomnia expressed by the patients with OSAS may have another mechanism. Less

  • Research Products

    (11 results)

All 2006 2005 2004

All Journal Article (9 results) Book (2 results)

  • [Journal Article] CSF hypocretin-1 measurement in pediatric and teenage patients with sleep disorders2006

    • Author(s)
      Yoshihiko KANEKO, Takashi KANBAYASHI, Tetsuo SHIMIZU
    • Journal Title

      Sleep and Biological Rhythms (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 古くて新しい巣症状 : 視床下部と過眠症状 : オレキシン神経系とナルコレプシー2005

    • Author(s)
      神林崇, 近藤英明, 清水徹男, 西野精治
    • Journal Title

      臨床神経学 45巻11号

      Pages: 824-827

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 過眠症の分子生物学2005

    • Author(s)
      神林崇, 清水徹男
    • Journal Title

      分子精神医学 5巻1号

      Pages: 23-31

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] ナルコレプシーおよびその周辺疾患の病態生理2005

    • Author(s)
      神林崇, 近藤英明, 佐藤伸介, 清水徹男
    • Journal Title

      Modern Physician 25巻1号

      Pages: 29-39

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The Anticataplectic Effect Of Milnacipran, A New Serotonin Noradrenaline Reuptake Inhibitor, On Human And Canine Narcolepsy2005

    • Author(s)
      Kaneko Y, Kanbayashi T, Shimizu T
    • Journal Title

      SLEEP 28

      Pages: A215

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] ナルコレプシーと他の過眠症における髄液中のヒスタミン2005

    • Author(s)
      神林崇, 児玉亨, 清水徹男
    • Journal Title

      第30回日本睡眠学会抄録集 30

      Pages: 222

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The Anticataplectic Effect Of Milnacipran, A New Serotonin Noradrenaline Reuptake Inhibitor, On Human And Canine Narcolepsy2005

    • Author(s)
      Kaneko Y, Kanbayashi T, _Shimizu T
    • Journal Title

      SLEEP 28

      Pages: A215

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] An old and new focal symptom, hypothalamus and hypersomnia, orexin system and narcolepsy2005

    • Author(s)
      Kanbayashi T, Kondo H, Shimizu T, Nishino S.
    • Journal Title

      Rinsho Shinkeigaku 45(11)

      Pages: 824-827

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] CSF Histamine And Noradrenaline Contents In Narcolepsy And Other Sleep Disorders2004

    • Author(s)
      Kanbayashi T, _Shimizu_T et al.
    • Journal Title

      SLEEP 27

      Pages: A236

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] Hypocretin Status in Neurological Disorders in Relation to Excessive Sleepiness and Cataplexy In : "Orexin/Hypocretin System, The Physiology and Pathophysiology" ((ed) Nishino S and Sakurai T)2006

    • Author(s)
      Kanbayashi T, Arii J, Kondo H, Shimizu T, Nishino S.
    • Total Pages
      30
    • Publisher
      Humana Press, Totowa, New Jersey, USA
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] Hypocretin Status in Neurological Disorders in Relation to Excessive Sleepiness and Cataplexy In : "Orexin/Hypocretin System, The Physiology and Pathophysiology" ((ed) Nishino S and Sakurai T)2005

    • Author(s)
      Kanbayashi T, Arii J, Kondo H, Shimizu T, Nishino S.
    • Total Pages
      287-316
    • Publisher
      Humana Press, Totowa, New Jersey, USA
    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2007-12-13  

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