European Archives of Oto-Rhino-Laryngology

, Volume 273, Issue 7, pp 1705–1710 | Cite as

Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menieres disease

  • M. Nue Møller
  • S. Kirkeby
  • J. Vikeså
  • F. Cilius Nielsen
  • P. Caye-Thomasen
Otology

Abstract

The human endolymphatic sac (ES) is situated in a duplicature of the dura in the posterior cranial fossa and constitutes a part of the inner ear. The sac possesses immunological capacities and is responsible for a major part of the trans-epithelial ion transport occurring within the inner ear, via molecular mechanisms similar to that of the kidney collecting duct epithelia. Dysfunction of the trans-epithelial ion transport has been hypothesized as the reason for the endolymphatic hydrops occurring in Menieres diseases. Thus, candidate drug selection for medical treatment of Menieres disease has been based on a potential capability of improving trans-epithelial ion transport. However, recent human studies seems to rule out diuretic therapy and The Committee for Medicinal Products for Human Use redrew the recommendation for trimetazidine (Vastarel) treatment in the management of Meniere disease in 2012. This leaves betahistine (Betaserc) as the only drug for potential prevention of the incapacitating attacks of dizziness, tinnitus and hearing loss. However, the histamine receptors targeted by betahistine have never been demonstrated in the human ES. Accordingly, this study aims to investigate the expression of histamine receptors of the human ES epithelium and sub-epithelial stroma. Following sampling of human endolymphatic sac tissue during translabyrinthine surgery, the expression of histamine receptor genes was determined by cDNA microarray analysis. Results were subsequently verified by immuno-histochemistry. The combined results of microarrays and immuno-histochemistry showed expression of the histamine receptor HRH1 in the epithelial lining of the ES, whereas HRH3 was expressed exclusively in the sub-epithelial capillary network. Receptors HRH2 and -4 were not expressed. The present data provide the first direct evidence of a molecular rationale for betahistine treatment in Menieres disease. A potential betahistine effect in Menieres disease may primarily be through the H3-receptor antagonism, leading to inhibition of vestibular neuro-transmission and central vaso-dilation. The H1-receptor localization in the ES epithelium suggests an immuno-regulatory effect.

Keywords

Inner ear Endolymphatic sac Meniere Betahistine Histamine receptor 

References

  1. 1.
    Kim SH, Marcus DC (2011) Regulation of sodium transport in the inner ear. Hear Res 280(1–2):21–29CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Salt AN, Plontke SK (2010) Endolymphatic hydrops. Pathophysiology and experimental models. Otolaryngol Clin North Am 43(5):971–983CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Møller MN, Caye-Thomasen P, Qvortrup K (2013) Oxygenated fixation demonstrates novel and improved ultrastructural features of the human endolymphatic sac. Laryngoscope 123(8):1967–1975. doi:10.1002/lary.23929 CrossRefPubMedGoogle Scholar
  4. 4.
    Møller MN, Kirkeby S, Vikeså J, Nielsen FC, Caye-Thomasen P (2015) Gene expression in the human endolymphatic sac: the solute carrier molecules in endolymphatic fluid homeostasis. Otol Neurotol 36(5):915–922. doi:10.1097/MAO.0000000000000669 CrossRefPubMedGoogle Scholar
  5. 5.
    Harris JP, Heydt J, Keithley EM, Chen MC (1997) Immunopathology of the inner ear: an update. Ann N Y Acad Sci 830:166–178CrossRefPubMedGoogle Scholar
  6. 6.
    Møller MN, Brandt C, Andersen C, Caye-Thomasen P (2015) Endolymphatic sac involvement in bacterial meningitis. Eur Arch Otorhinolaryngol 272(4):843–851. doi:10.1007/s00405-014-2884-y CrossRefPubMedGoogle Scholar
  7. 7.
    Møller MN, Kirkeby S, Vikeså J, Nielsen FC, Caye-Thomasen P (2015) Gene expression demonstrates an immunological capacity of the human endolymphatic sac. Laryngoscope. doi:10.1002/lary.25242 PubMedGoogle Scholar
  8. 8.
    Schuknecht HF, Suzuka Y, Zimmermann C (1990) Delayed endolymphatic hydrops and its relationship to Meniére’s disease. Ann Otol Rhinol Laryngol 99(11):843–853CrossRefPubMedGoogle Scholar
  9. 9.
    Merchant SN, Adams JC, Nadol JB Jr (2005) Pathophysiology of Meniere’s syndrome: are symptoms caused by endolymphatic hydrops? Otol Neurotol 26(1):74–81CrossRefPubMedGoogle Scholar
  10. 10.
    Lacour M, van de Heyning PH, Novotny M, Tighilet B (2007) Betahistine in the treatment of Ménière’s disease. Neuropsychiatr Dis Treat 3(4):429–440PubMedPubMedCentralGoogle Scholar
  11. 11.
    Phillips JS, Westerberg B (2011) Intratympanic steroids for Ménière’s disease or syndrome. Cochrane Database Syst Rev 6(7):CD008514. doi:10.1002/14651858.CD008514.pub2 Google Scholar
  12. 12.
    Lambert PR, Nguyen S, Maxwell KS, Tucci DL, Lustig LR, Fletcher M, Bear M, Lebel C (2012) A randomized, double-blind, placebo-controlled clinical study to assess safety and clinical activity of OTO-104 given as a single intratympanic injection in patients with unilateral Ménière’s disease. Otol Neurotol 33(7):1257–1265. doi:10.1097/MAO.0b013e318263d35d CrossRefPubMedGoogle Scholar
  13. 13.
    Ihler F, Bertlich M, Sharaf K, Strieth S, Strupp M, Canis M (2012) Betahistine exerts a dose-dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo. Plos One 7(6):e39086. doi:10.1371/journal.pone.0039086 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dagli M, Goksu N, Eryilmaz A, Mocan Kuzey G, Bayazit Y, Gun BD, Gocer C (2008) Expression of histamine receptors (H(1), H(2), and H(3)) in the rabbit endolymphatic sac: an immunohistochemical study. Am J Otolaryngol 29(1):20–23CrossRefPubMedGoogle Scholar
  15. 15.
    Malinowska B, Godlewski G, Schlicker E (1998) Histamine H3 receptors–general characterization and their function in the cardiovascular system. J Physiol Pharmacol 49(2):191–211PubMedGoogle Scholar
  16. 16.
    Tighilet B, Mourre C, Trottier S, Lacour M (2007) Histaminergic ligands improve vestibular compensation in the cat: behavioural, neurochemical and molecular evidence. Eur J Pharmacol 568:149–163CrossRefPubMedGoogle Scholar
  17. 17.
    Tighilet B, Trottier S, Lacour M (2005) Dose- and duration-dependent effects of betahistine dihydrochloride treatment on histamine turnover in the cat. Eur J Pharmacol 523:54–63CrossRefPubMedGoogle Scholar
  18. 18.
    Tighilet B, Trottier S, Mourre C, Chotard C, Lacour M (2002) Betahistine dihydrochloride interaction with the histaminergic system in the cat: neurochemical and molecular mechanisms. Eur J Pharmacol 446:63–73CrossRefPubMedGoogle Scholar
  19. 19.
    Zhou L, Zhou W, Zhang S, Liu B, Leng Y, Zhou R, Kong W (2013) Changes in histamine receptors (H1, H2, and H3) expression in rat medial vestibular nucleus and flocculus after unilateral labyrinthectomy: histamine receptors in vestibular compensation. Plos One 8(6):e66684CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Soto E, Vega R (2010) Neuropharmacology of vestibular system disorders. Curr Neuropharmacol 8(1):26–40CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hu WW, Chen Z (2012) Role of histamine and its receptors in cerebral ischemia. ACS Chem Neurosci 3(4):238–247. doi:10.1021/cn200126p CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gbahou F, Davenas E, Morisset S, Arrang JM (2010) Effects of betahistine at histamine H3 receptors: mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo. J Pharmacol Exp Ther 334(3):945–954. doi:10.1124/jpet.110.168633 CrossRefPubMedGoogle Scholar
  23. 23.
    Yabe T, de Waele C, Serafin M, Vibert N, Arrang JM, Mühlethaler M, Vidal PP (1993) Medial vestibular nucleus in the guinea-pig: histaminergic receptors. II. An in vivo study. Exp Brain Res 93:249–258CrossRefPubMedGoogle Scholar
  24. 24.
    Mukhopadhyay S, Niyogi M, Ray R, Mukhopadhyay BS, Dutta M, Mukherjee M (2013) Betahistine as an add-on: the magic bullet for postoperative nausea, vomiting and dizziness after middle ear surgery? J Anaesthesiol Clin Pharmacol 29(2):205–210. doi:10.4103/0970-9185.111725 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lacour M (2013) Betahistine treatment in managing vertigo and improving vestibular compensation: clarification. J Vestib Res 23(3):139–151. doi:10.3233/VES-130496 PubMedGoogle Scholar
  26. 26.
    Müller T, Myrtek D, Bayer H, Sorichter S, Schneider K, Zissel G, Norgauer J, Idzko M (2006) Functional characterization of histamine receptor subtypes in a human bronchial epithelial cell line. Int J Mol Med 18(5):925–931PubMedGoogle Scholar
  27. 27.
    Kim HM, Lee CH, Rhee CS (2012) Histamine regulates mucin expression through H1 receptor in airway epithelial cells. Acta Otolaryngol 132(Suppl 1):S37–S43. doi:10.3109/00016489.2012.661075 CrossRefPubMedGoogle Scholar
  28. 28.
    Nguyen TD, Okolo CN, Moody MW (1998) Histamine stimulates ion transport by dog pancreatic duct epithelial cells through H1 receptors. Am J Physiol 275(1 Pt 1):G76–G84PubMedGoogle Scholar
  29. 29.
    Furukawa M, Suzuki H, Ikeda K, Oshima T, Yamaya M, Sasaki H, Takasaka T (1999) Kinin and histamine stimulate Cl- secretion in gerbil middle ear epithelium: connection to otitis media. Hear Res 132(1):109–116CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • M. Nue Møller
    • 1
  • S. Kirkeby
    • 2
  • J. Vikeså
    • 3
  • F. Cilius Nielsen
    • 3
    • 4
  • P. Caye-Thomasen
    • 1
    • 4
  1. 1.Department of Oto-rhino-laryngology, Head and Neck Surgery, and AudiologyCoepnhagen University Hospital RigshospitaletCopenhagenDenmark
  2. 2.Department of Oral Medicine, Dental School, Panum InstituteUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Clinical BiochemistryRigshospitalet, University of CopenhagenCopenhagenDenmark
  4. 4.Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations