Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menieres disease
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.
KeywordsInner ear Endolymphatic sac Meniere Betahistine Histamine receptor
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Conflict of interest
The authors report no conflict of interest.
- 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
- 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
- 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