Morphological and functional changes in a new animal model of Ménière's disease

Abstract

The purpose of this study was to clarify the underlying mechanism of vertiginous attacks in Ménière's disease (MD) while obtaining insight into water homeostasis in the inner ear using a new animal model. We conducted both histopathological and functional assessment of the vestibular system in the guinea-pig. In the first experiment, all animals were maintained 1 or 4 weeks after electrocauterization of the endolymphatic sac of the left ear and were given either saline or desmopressin (vasopressin type 2 receptor agonist). The temporal bones from both ears were harvested and the extent of endolymphatic hydrops was quantitatively assessed. In the second experiment, either 1 or 4 weeks after surgery, animals were assessed for balance disorders and nystagmus after the administration of saline or desmopressin. In the first experiment, the proportion of endolymphatic space in the cochlea and the saccule was significantly greater in ears that survived for 4 weeks after surgery and were given desmopressin compared with other groups. In the second experiment, all animals that underwent surgery and were given desmopressin showed spontaneous nystagmus and balance disorder, whereas all animals that had surgery but without desmopressin administration were asymptomatic. Our animal model induced severe endolymphatic hydrops in the cochlea and the saccule, and showed episodes of balance disorder along with spontaneous nystagmus. These findings suggest that administration of desmopressin can exacerbate endolymphatic hydrops because of acute V2 (vasopressin type 2 receptor)-mediated effects, and, when combined with endolymphathic sac dysfunction, can cause temporary vestibular abnormalities that are similar to the vertiginous attacks in patients with MD. Ménière's disease (MD) is a well-known inner ear disorder characterized by symptoms including recurring attacks of vertigo typically lasting for hours, fluctuating sensorineural hearing loss, and tinnitus. Since the milestone findings on the temporal bones of MD patients, 1,2 endolymphatic hydrops (EH) has been considered as the histopathological origin of MD, as characteristic morphological changes were reported to be produced by surgical obstruction of the endolymphatic sac (ES) in guinea-pig. 3 This observation indicates that malabsorption of endolymph in the ES is one of the possible mechanisms underlying the development of EH. This experimentally induced EH has been frequently used as an animal model to investigate the pathogenesis of inner ear disorders associated with EH. In terms of vestibular function, while canal dysfunction and/or spontaneous nystagmus have been occasionally observed in this animal model, 4,5 episodes of vertiginous attack or balance disorder have only rarely been observed. 6 In other words, this model is insufficient for fully representing the common symptoms of MD.Water homeostasis of the inner ear is essential for maintaining the functions of hearing and balance. EH is considered to be the result of disruption of inner ear water homeostasis, which ...

Ménière's Disease Treatment: A Patient-Centered Systematic Review

“…Understanding the mechanisms underlying the pathophysiology of cochlear microcirculation is of fundamental clinical importance for Ménière's disease. The etiopathogenic role of vasopressin imbalance in the stria vascularis affecting microcirculation was recently elucidated in experimental animal models [Egami et al, 2013;Kakigi, 2013], becoming a promising target of new etiologic therapies [Naganuma, 2013]. Obstruction of the distal part of the vein of the vestibular aqueduct in experimental animals causes disturbances in the endolymph homeostasis and potentially symptoms similar to the ones of Ménière's disease [Friis and Qvortrup, 2007], confirming previous observations in humans affected by Ménière's disease who presented with occlusion of the vein of the vestibular aqueduct.…”

Secondary Endolymphatic Hydrops

“…Recently investigated reasons for SEH include traumatic injury, such as post-operative trauma following cochlear implantation (4–6) and stapedectomy for otosclerosis (7); ablation of the endolymphatic sac (8,9); and acoustic and mechanical trauma (2). Medications, including vasopressin (1,8), have also been associated with development of SEH.…”

A possible mechanism of the formation of endolymphatic hydrops and its associated inner ear disorders

“…This means that the secretary function seems to be dominant in the AVP-V2R-AQP2 axis of the inner ear. Further, the degree of AVP-induced hydrops becomes more pronounced by the obstruction of the ES with the absorption function [6]. Although EH is confirmed to manifest within one hour after a one-shot subcutaneous injection of AVP [109], longitudinal development of AVPinduced EH is not yet well-documented.…”

“…It is likely that vertiginous attack presented by Uchida et al was caused by abrupt over-production of endolymph resulting from histamine-induced elevation of p-AVP level [5]. Indeed, Egami et al, made clear the role of vasopressin in the endolymph homeostasis and its close contact with inner ear function; administration of desmopressin (a VP type 2 receptor agonist) can exacerbate EH because of acute V2 (vasopressin type 2 receptor)-mediated effects, and, when combined with ES dysfunction, can cause temporary vestibular abnormalities that are similar to the vertiginous attacks in patients with MD [6]. Recently, Kim et al also confirmed that this application of the vasopressin type 2 receptor agonist in experimentally-induced EH produced asymmetric vestibular dysfunction in bidirectional sinusoidal harmonic acceleration test, similar to bidirectional nystagmus in MD [165].…”

“…But, there are two reports to succeed to evoke vertiginous attack in animals with the surgically-induced dysfunction of the endolymphatic sac (ES): (1) an intraperitoneal injection of histamine in guinea pigs with immunologically-obliterated ES [5], (2) a subcutaneous injection of desmopressin in guinea pigs with electrocauterization of the ES [6]. A common denominator of these two experimental animals is that an abrupt increase in the endolymphatic volume is found by the administration of Auris Nasus Larynx 47 (2020) [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] histamine or desmopressin.…”