Histaminergic System and Vestibular Function in Normal and Pathological Conditions.

Most neurotransmitter systems are represented in the central and peripheral vestibular system and are thereby involved both in normal vestibular signal processing and the pathophysiology of vestibular disorders. However, there is a special relationship between the vestibular system and the histaminergic system. The purpose of this review is to document how the histaminergic system interferes with normal and pathological vestibular function. In particular, we will discuss neurobiological mechanisms such as neuroinflammation that involve histamine to modulate and allow restoration of balance function in the situation of a vestibular insult. These adaptive mechanisms represent targets of histaminergic pharmacological compounds capable of restoring vestibular function in pathological situations. The clinical use of drugs targeting the histaminergic system in various vestibular disorders is critically discussed.

The Role of Steroids in the Preservation of Hearing and Vestibular Function in Cochlear Implantation.

OBJECTIVE: Cochlear implant surgery is guided by principles of atraumatic insertion as to protect the inner ear. Previous studies suggest the potential benefit of steroids in patients undergoing cochlear implantation (CI), although the optimal route of administration has yet to be determined. We aim to systematically review the human studies of hearing and vestibular function preservation in patients undergoing CI receiving perioperative steroids and to discuss their role. DATA SOURCES: Search performed in PubMed, EMBASE, and CENTRAL databases in December 2023. REVIEW METHODS: Studies comparing several methods of steroid delivery and conventional management for patients undergoing CI were identified. Primary outcomes included hearing and vestibular function preservation. Secondary outcomes included reported adverse events, routes of steroid administration, and the presence of a control group without steroid administration. RESULTS: A total of 15 studies (N = 659) met inclusion criteria. Methodology, doses, route of steroid administration, and follow-up duration differed between most studies. Audiometric, vestibular, and hearing preservation (HP) results were inconsistent. In 12 studies, perioperative steroids were associated with either increased HP or vestibular function preservation. Only two studies reported adverse events related to oral corticosteroid therapy. CONCLUSIONS: There is a tendency for perioperative steroids to have a positive impact, at least in the short term, on hearing and vestibular function preservation in CI. Topical corticosteroid therapy appears to have a superior risk-benefit profile. There is a need for future carefully designed randomized controlled trials to determine the ideal route of steroid administration and its real impact in the long term. Laryngoscope, 134:3458-3465, 2024.

A Vestibular Challenge Combined with Calcitonin Gene-Related Peptide (CGRP) Promotes Anxiety-Like Behaviors.

Motion-induced anxiety and agoraphobia are more frequent symptoms in patients with vestibular migraine (VM) than migraine without vertigo. The neuropeptide calcitonin gene-related peptide (CGRP) is a therapeutic target for migraine and VM, but the link between motion hypersensitivity, anxiety, and CGRP is relatively unexplored, especially in preclinical mouse models. To further examine this link, we tested the effects of systemic CGRP and off-vertical axis rotation (OVAR) on elevated plus maze (EPM) and rotarod performance in male and female C57BL/6J mice. Rotarod ability was assessed using two different dowel diameters: mouse dowel (r = 1.5 cm) versus rat dowel (r = 3.5 cm). EPM results indicate that CGRP alone or OVAR alone did not increase anxiety indices. However, the combination of CGRP and OVAR did elicit anxiety-like behavior. On the rotarod, CGRP reduced performance in both sexes on a mouse dowel but had no effect on a rat dowel, whereas OVAR had a significant effect on the rat dowel. These results suggest that only the combination of CGRP with vestibular stimulation induces anxiety-like behavior and that CGRP affects the dynamic balance function in mice depending on the type of challenge presented. These findings suggest that anxiety-like behaviors can be teased out from imbalance behaviors in a mouse model of "migraine." Future studies are aimed to determine if CGRP receptor antagonists that have been effective treating migraineurs and mouse "migraine" models may also reduce the anxiety observed in migraine.

Trauma-Induced Vestibular Dysfunction: Improved Repair Under Local Treatment With α1-Antitrypsin.

AIM: To characterize vestibular recovery in a mouse model of unilateral labyrinthotomy under local AAT and dexamethasone treatment. BACKGROUND: Alpha1-antitrypsin (AAT) is a circulating tissue-protective molecule that rises during inflammatory conditions and promotes inflammatory resolution. Its local concentration in human perilymph inversely correlates with the severity of inner ear dysfunction; concomitantly, mice that overexpress AAT and undergo inner ear trauma rapidly restore vestibular function. Locally applied AAT has yet to be examined in this context, nor has it been directly compared with anti-inflammatory corticosteroid treatment. METHODS: Wild-type mice C57BL/6 underwent a unilateral inner ear injury. Nine microliters of saline, clinical-grade AAT (180 µg/site), dexamethasone (4 mg/site), or both were applied locally on Days 0, 1, and 2 (n = 5/group). Vestibular function was assessed for 7 days. An in vitro human epithelial gap closure assay was performed using A549 cells in the presence of AAT and/or dexamethasone. RESULTS: Upon labyrinthotomy, all groups displayed severe vestibular dysfunction. Saline-treated mice showed the longest impairment. That group and the dexamethasone group displayed partial to no recovery, while AAT-treated mice exhibited complete recovery within 7 days; at this time point, dexamethasone-treated mice exhibited 50% recovery. Objective vestibular testing showed similar outcomes. In vitro, cotreatment with AAT and dexamethasone resulted in a gap closure dynamic that was superior to AAT alone at 6 h and superior to DEX alone at 48 h. CONCLUSION: Locally applied AAT treatment is superior to locally applied dexamethasone in promoting vestibular recovery in vivo. Ongoing studies are exploring the potential advantages of AAT combined with early low-dose dexamethasone therapy.

Morphological analysis of the vestibular system of guinea pigs poisoned by organophosphate / Análise morfológica do sistema vestibular de cobaias intoxicadas por organofosforado

ABSTRACT INTRODUCTION: The vestibular system is responsible for body balance. There are substances that damage it, causing dizziness; these are termed vestibulotoxic substances. Agrochemicals have been investigated for ototoxicity because of studies that identified dizziness as a recurrent symptom among rural workers' complaints. OBJECTIVE: To histopathologically evaluate the vestibular system in guinea pigs exposed to an organophosphate, and to identify the drug's effects on this system. METHODS: Experimental clinical study. Eighteen guinea pigs were used; six of them poisoned with the organophosphate chlorpyrifos at doses of 0.5 mg/kg/day and seven of them at 1 mg/kg/day; and a control group of five guinea pigs was exposed to distilled water, all for 10 consecutive days. Later, ciliary tufts of saccule and utricle maculae were counted by scanning electron microscopy. RESULTS: Comparing the groups, a one-way ANOVA test for the variable "saccule" ( p = 0.0569) and a Kruskal-Wallis test for the variable "utricle" ( p = 0.8958) were performed, revealing no difference among groups in both variables. CONCLUSION: The histopathologic analysis of the vestibular system of guinea pigs exposed to an organophosphate showed no difference in the amount of ciliary tufts of saccule and utricle maculae at the doses tested, although the result for the variable "saccule" was considered borderline, showing a trend for significance.

RESUMO INTRODUÇÃO: O sistema vestibular é responsável pelo equilíbrio corporal. Existem substâncias que o danificam, causando tontura; são chamadas vestibulotóxicas. Agrotóxicos tornaram-se objeto de investigação da ototoxicidade a partir de pesquisas que apontaram tontura como sintoma recorrente entre as queixas de trabalhadores rurais. OBJETIVO: Constitui-se em avaliar a histopatologia do sistema vestibular de cobaias expostas a organofosforados, identificando os efeitos nesse sistema. MÉTODO: É um estudo clínico experimental, que utilizou 18 cobaias, sendo seis intoxicadas com organofosforadoclorpirifós na dose de 0,5 mg/kg/dia; sete na dose de 1 mg/kg/dia, e grupo controle com cinco cobaias expostas a água destilada, durante 10 dias consecutivos. Posteriormente realizou-se a contagem dos tufos ciliares nas máculas dos sáculos e utrículos através microscopia eletrônica de varredura. RESULTADOS: Na comparação intergrupos, para a variável sáculo realizou-se o teste ANOVA one-way (p = 0,0569); para a variável utrículo, utilizou-se o teste Kruskal-Wallis (p = 0,8958), revelando não haver diferença entre os grupos em ambas as variáveis. CONCLUSÃO: Análise histopatológica do sistema vestibular de cobaias expostas a organofosforado não demonstrou diferença na quantidade de tufos ciliares nas máculas dos sáculos e utrículos nas doses testadas, apesar do resultado para a variável sáculo ser considerado limítrofe mostrando uma tendência a significância.

Ototoxicidade por organofosforados: descrição dos aspectos ultraestruturais do sistema vestibulococlear de cobaias / Organophosphate-related ototoxicity: Description of the vestibulocochlear system ultrastructural aspects of guinea pigs

Os agrotóxicos organofosforados são amplamente utilizados na agricultura, e atualmente fazem parte do grupo de agentes químicos que podem levar à perda auditiva, no qual já estavam incluídos os solventes, os metais e os asfixiantes. OBJETIVO: Analisar a ação ototóxica aguda de um agrotóxico do grupo dos organofosforados na citoarquitetura do sistema vestibulococlear. Trata-se de um estudo experimental prospectivo. MATERIAL E MÉTODO: Foram utilizadas cobaias albinas machos, divididas em três grupos, nos quais se administrou água destilada (grupo 1 - controle), agrotóxico - 0,3mg/Kg/dia (grupo 2), agrotóxico - 3 mg/Kg/dia (grupo 3), durante sete dias consecutivos. O agrotóxico utilizado foi Tamaron BR (metamidofós). A avaliação anatômica da cóclea, sáculo e utrículo foi realizada através da microscopia eletrônica de varredura, após o período de aplicação do agrotóxico. RESULTADOS: As cobaias submetidas ao organofosforado apresentaram alterações morfológicas cocleares, com lesões nas três espiras analisadas, bem como alterações ciliares de sáculo e utrículo, intensificadas de acordo com a dosagem recebida do agente. CONCLUSÃO: As alterações morfológicas observadas nas células ciliadas nos grupos expostos a doses diárias de organofosforado promovem evidências de um efeito agudo degradante dos agrotóxicos no sistema vestibulococlear.

Organophosphate toxic agents are used in agriculture and are currently part of the group of toxic agents which can lead to hearing loss, in which we have solvents, metals and asphyxiation agents. AIM: to analyze the acute ototoxic action of a group of organophosphate agents in the vestibulo-cochlear system. This is a prospective experimental study. MATERIALS AND METHODS: we used male albino guinea pigs, broken down into three groups, to which we provided distilled water (group 1 - control), agrotoxic agent - 0.3mg/Kg/day (group 2), agrotoxic - 3 mg/Kg/day (group 3), during 7 seven consecutive days. The most used agrotoxic agent was Tamaron BR (metamidophos). The anatomical evaluation of the cochlea, saccule and utricle was carried out by means of electronic scanning microscopy after the use of the agrotoxic agent. RESULTS: the guinea pigs submitted to the organophosphate presented cochlear morphological alterations with lesions on the three turns analyzed, as well as cilia alterations in the saccule and utricle, intensified according to the agent dosage. CONCLUSION: the morphological alterations seen in the hair cells exposed to daily doses of organophosphate promote evidences of an acute deleterious effect of agrotoxic agents on the vestibulo-cochlear system.

Alfa-Glucosidasa con Posible Acción Hidrolítica Sobre Aminoglicósidos en la Sangre y el Vestíbulo de Ratas / Alpha-glucosidase with possible hydrolytic action over aminoglycosides in the blood and vestibule of rats

Antecedentes e hipótesis. La estreptomicina (STP)es un antibiótico aminoglicósido que se usa en el tratamiento de la tuberculosis, con efectos tóxicos importantes sobre la función vestibular. Los antecedentes farmacocinéticos muestran que la STP se acumula en un principio en la parte perilinfática y por mecanismos aún no descritos pasa a la endolinfa donde su principal blanco de acción son los cilios sensorios de las células pilosas vestibulares. Consideramos importante averiguar que parte de la molécula de STP es la responsable de su toxicidad vestibular, y tenemos evidencias que señalan la parte estreptidina (STD)como la porción activa, por lo que se propone que la STP actúa fragmentada por acción de una alfa-glucosidasa que hidroliza el enlace -1,4 con la liberación de la STD y que esté presente ya sea en el vestíbulo, en el torrente sanguíneo o en ambos. Método. Se determinó la actividad de alfa-glucosidasa en el suero y en homogeneizado vestibular de la rata usando p-nitrofenil--d-glucósido como sustrato; siguiendo el p-nitrofenilo (pNP)liberado espectrofotométricamente a 400 nm. Resultados. Se encontró alfa-glucosidasa tanto en el suero como en el vestíbulo de la rata con actividades específicas de 0.035 y 1.3 nmol de pNP/mg proteína/min respectivamente. Conclusión. La actividad encontrada en vestíbulo es semejante a la de la alfa-glucosidasa lisosomal del hígado de la rata (1.5 nmol de pNP/mg proteína/min)por lo que es posible que la alfa-glucosidasa presente en el suero y en el vestíbulo pueda romper a la STP, liberando la parte STD que actuaría sobre el oído

Estreptomicina: propiedades fisicoquímicas y toxicidad vestibular / Streptomycin, physical and chemical characteristics and vestibular toxicity

Propósito: Los antibióticos aminoglucósidos estreptomicina (STP) y kanamicina (KAN) son tóxicos para las células sensoriales del vestíbulo y de la cóclea, respectivamente. Químicamente están constituidos por estreptidina (STD) un derivado del inositol y dos azúcares, la esteptosa (Stosa) y la N-metilglucosamida (nm-GLUN); sin embargo, en la STP, la STD tiene dos sustituyentes guanidino, los que están ausentes en la KAN. Por lo tanto, se propone estudiar si la vestíbulo-toxicidad específica de la STP se debe a los grupos guanidino. Material y Métodos: Se incubaron en vitro, membranas celulares aisladas de los órganos vestibulares, con 3H-espermidina (3H-Spdina), un análogo estructural de la STP. Se midió la capacidad de los siguientes compuestos: STP, STD, KAN, guanidina (GUA) y n-acetilglucosamina (na-GLUN) para desplazarlos específicamente. Resultados: Se encontró que el orden de desplazamiento de la 3HSPdina para esas sustancia era STP=STD KanGUAn-a-GLUN. Conclusiones: Los resultados sugieren fuertemente que la STP debe su especificidad vestibulotóxica, a la presencia de los grupos guanidino en la porción de STD de su molécula, los que interactuarían por sus cargas positivas con estructuras membranales vestibulares relacionadas con la transducción, muy probablemente los cilios sensorios de las células ciliadas vestibulares

Da avaliaçäo vestibular em 42 pacientes com ototoxicose / Vestibular evaluation in 42 patients with ototoxicosis

This investigation was developed in "Setor de Equilibriometria das Disciplinas de Otorrinolaringologia e Distúrbios da Comunicaçäo Humana da Escola Paulista de Medicina" and it consisted in the vestivular evaluation of 42 patients treated with gentamycin. The vestibular evaluation was performed and measured according ro MANGABEIRA ALBERNAZ e col., (l986) and in this paper we related the analysis of rotatory and caloric reponses. In facing our study we concluded that the most frequent signals were hiporreflexia or absence of responses in rotatory and caloric tests that indicates the deficit on the vestibular function in these patients

Ototoxicidade de drogas medicamentosas / Ototoxicity of drugs

Os medicamentos ototóxicos, sendo os antibióticos aminoglicosídeos mais comuns, podem provocar lesöes irreversíveis nas células ciliadas do órgäo de Corti e das máculas e cristas do sistema vestibular. A lesäo celular está relacionada com a formaçäo de substâncias complexas entre a droga ototóxica e os polifosfoinositídeos da membrana celular. O controle das funçöes auditiva e vestibular deve ser permanente durante a utilizaçäo desses medicamentos, sobretudo se existem fatores de risco. Experimentalmente, as lesöes induzidas têm sido estudadas em animais por métodos eletrofisiológicos, com registro dos potenciais colcleares e dos potenciais do tronco cerebral, e por métodos histológicos, com técnicas de preparaçäo de superfície do órgäo de Corti, microscopia eletrônica e isolamento de células ciliadas em meio de cultura

Aminoglucósidos, su efecto ototóxico / Aminoglucosides. The ototoxcic effect

Los aminoglucósidos son antibióticos de amplio espectro, especialmente útiles contra microorganismos gramnegativos aerobios. Desde que se introdujo la estreptomicina para el tratamiento de la tuberculosis se identificaron sus posibles efectos tóxicos. Todos los antibióticos de este grupo pueden provocar toxicidad renal, coclear y/o vestibular. El daño renal generalmente es reversible, pero el daño al epitelio sensorial que producen en el oído interno es irreversible. Se ha sugerido que la interferencia con la síntesis de proteínas es el mecanismo central de su toxicidad. En los últimos 50 años, se han identificado factores de riesgo para que la ototoxicidad se presente, incluyendo una forma de hipersensibilidad hereditaria. Aunque se han propuesto estrategias para prevenir del daño, aún es común observar pacientes con sordera y desequilibrio secundarios a la administración de aminoglucósidos. En este documento se ofrece una revisión resumida sobre el efecto ototóxico de los aminoglucósidos. Se comentan algunas estrategias para su prevención y la aplicación terapéutica del efecto vestibulotóxico