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1.
Am J Otolaryngol ; 41(5): 102579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32531621

RESUMO

AIM: The aim of the present study was to evaluate the effect of isotretinoin (ISO) on peripheral vestibular system using vHIT. MATERIAL AND METHOD: This is a prospective study in which 30 patients administered ISO treatment with the diagnosis of acne vulgaris was evaluated. Following ear nose and throat, examination, audiological and vestibular evaluations were carried out. vHIT tests were conducted before and three months after the use of ISO (0.5-0.75 mg/kg/day). In addition, all participants underwent perceptual vertigo and dizziness tests before and three months after the use of ISO. RESULTS: In vHIT evaluation of all patients, no overt saccade, covert saccade and spontaneous nystagmus finding was observed. Gain and asymmetry were compared before and after the use of ISO: No significant difference was found between lateral semicircular canal, anterior, and posterior semi-circular and symmetry measurements made before ISO use and those made three months after it (p = 1.00; p = 0.99; p = 0.66). Similarly, there was no significant difference in asymmetry values of vertical semicircular canals measured before ISO and three months after it (p = 0.90; p = 0.76). No statistically significant difference was found in vertigo, nausea and dizziness in terms of responses before and 3 months after ISO use (p = 0.063; p = 0.031; p = 0.063). CONCLUSION: Although the studies demonstrating the effect of ISO on cochlea and symptoms occurring during treatment such as nausea, vomiting and vertigo suggest that it may exert effects on peripheral vestibular system, the present study indicates that it has no short terms effects on structures in peripheral vestibular system and vestibuloocular reflex pathways.


Assuntos
Acne Vulgar/tratamento farmacológico , Técnicas de Diagnóstico Otológico , Isotretinoína/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Isotretinoína/uso terapêutico , Masculino , Náusea/induzido quimicamente , Estudos Prospectivos , Reflexo Vestíbulo-Ocular/efeitos dos fármacos , Canais Semicirculares/efeitos dos fármacos , Canais Semicirculares/patologia , Vertigem/induzido quimicamente , Vestíbulo do Labirinto/efeitos dos fármacos , Vômito/induzido quimicamente , Adulto Jovem
2.
Nucleic Acids Res ; 48(9): 5065-5080, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32249312

RESUMO

Disabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13-13.5 (E13-13.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Surdez/congênito , Surdez/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Vestíbulo do Labirinto/fisiopatologia , Âmnio , Animais , Limiar Auditivo/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Surdez/genética , Surdez/fisiopatologia , Orelha Interna/efeitos dos fármacos , Orelha Interna/metabolismo , Feto , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/ultraestrutura , Camundongos , Microinjeções , Mutação , Oligonucleotídeos Antissenso/administração & dosagem , Splicing de RNA/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos
3.
Exp Parasitol ; 206: 107768, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539540

RESUMO

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.


Assuntos
Alopurinol/efeitos adversos , Doenças do Cão/tratamento farmacológico , Audição/efeitos dos fármacos , Rim/efeitos dos fármacos , Leishmaniose Visceral/veterinária , Paromomicina/efeitos adversos , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Animais , Cóclea/efeitos dos fármacos , Creatinina/sangue , Doenças do Cão/parasitologia , Cães , Método Duplo-Cego , Combinação de Medicamentos , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/veterinária , Injeções Subcutâneas/veterinária , Leishmania infantum , Leishmaniose Visceral/tratamento farmacológico , Masculino , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/efeitos adversos , Antimoniato de Meglumina/uso terapêutico , Exame Neurológico/veterinária , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Distribuição Aleatória , Vestíbulo do Labirinto/efeitos dos fármacos
4.
J Assoc Res Otolaryngol ; 20(6): 553-563, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31297642

RESUMO

The tail-lift reflex and the air-righting reflex are anti-gravity reflexes in rats that depend on vestibular function. To obtain objective and quantitative measures of performance, we recorded these reflexes with slow-motion video in two experiments. In the first experiment, vestibular dysfunction was elicited by acute exposure to 0 (control), 400, 600, or 1000 mg/kg of 3,3'-iminodipropionitrile (IDPN), which causes dose-dependent hair cell degeneration. In the second, rats were exposed to sub-chronic IDPN in the drinking water for 0 (control), 4, or 8 weeks; this causes reversible or irreversible loss of vestibular function depending on exposure time. In the tail-lift test, we obtained the minimum angle defined during the lift and descent maneuver by the nose, the back of the neck, and the base of the tail. In the air-righting test, we obtained the time to right the head. We also obtained vestibular dysfunction ratings (VDRs) using a previously validated behavioral test battery. Each measure, VDR, tail-lift angle, and air-righting time demonstrated dose-dependent loss of vestibular function after acute IDPN and time-dependent loss of vestibular function after sub-chronic IDPN. All measures showed high correlations between each other, and maximal correlation coefficients were found between VDRs and tail-lift angles. In scanning electron microscopy evaluation of the vestibular sensory epithelia, the utricle and the saccule showed diverse pathological outcomes, suggesting that they have a different role in these reflexes. We conclude that these anti-gravity reflexes provide useful objective and quantitative measures of vestibular function in rats that are open to further development.


Assuntos
Gravitação , Reflexo/fisiologia , Vestíbulo do Labirinto/fisiologia , Animais , Relação Dose-Resposta a Droga , Masculino , Nitrilas/toxicidade , Ratos , Ratos Long-Evans , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/patologia
5.
Acta Otolaryngol ; 139(9): 759-768, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31311369

RESUMO

Objectives: To determine the incidence of gentamicin vestibulotoxicity with current dosing regimens, and to evaluate the feasibility of routine video-oculography on all patients given gentamicin. Materials and methods: In this prospective incidence study serial horizontal vestibulo-ocular reflex (HVOR) gain measurements were recorded using video-oculography on adult inpatients receiving intravenous gentamicin. The primary outcome was the proportion of patients developing impairment of their HVOR gain. Results: After exclusions, 42 patients were included in the analysis. Three patients (7.1%) developed asymptomatic vestibulotoxicity, exact 95% confidence interval 1.5-19.5%. In two of these patients the deficit resolved within several hours. No patients developed symptomatic vestibulotoxicity. There was no evidence for a generalised reduction in group HVOR gain with time. HVOR gain was not associated with total gentamicin dose, dynamic visual acuity or subjective imbalance. Conclusions and significance: Gentamicin may cause reversible, asymptomatic vestibulotoxicity. Video-oculography may be useful to monitor for vestibulotoxicity in patients treated with gentamcin; however, testing all patients routinely may be challenging.


Assuntos
Gentamicinas/efeitos adversos , Ototoxicidade/etiologia , Reflexo Vestíbulo-Ocular/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Gravação em Vídeo , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Gentamicinas/uso terapêutico , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Ototoxicidade/diagnóstico , Estudos Prospectivos , Medição de Risco , Centros de Atenção Terciária , Doenças Vestibulares/induzido quimicamente
6.
J Neurol ; 266(Suppl 1): 93-100, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270663

RESUMO

Vestibulo-ocular reflexes (VOR) are mediated by frequency-tuned pathways that separately transform the different dynamic and static aspects of head motion/position-related sensory signals into extraocular motor commands. Voltage-dependent potassium conductances such as those formed by Kv1.1 are important for the ability of VOR circuit elements to encode highly transient motion components. Here we describe the impact of the Kv1.1 channel blocker 4-aminopyridine (4-AP) on spontaneous and motion-evoked discharge of superior oblique motoneurons. Spike activity was recorded from the motor nerve in isolated preparations of Xenopus laevis tadpoles. Under static conditions, bath application of 1-10 µM 4-AP increased the spontaneous firing rate and provoked repetitive bursts of spikes. During motion stimulation 4-AP also augmented and delayed the peak firing rate suggesting that this drug affects the magnitude and timing of vestibular-evoked eye movements. The exclusive Kv1.1 expression in thick vestibular afferent fibers in larval Xenopus at this developmental stage suggests that the altered extraocular motor output in the presence of 4-AP mainly derives from a firing rate increase of irregular firing vestibular afferents that propagates along the VOR circuitry. Clinically and pharmacologically, the observed 4-AP-mediated increase of peripheral vestibular input under resting and dynamic conditions can contribute to the observed therapeutic effects of 4-AP in downbeat and upbeat nystagmus as well as episodic ataxia type 2, by an indirect increase of cerebellar Purkinje cell discharge.


Assuntos
4-Aminopiridina/administração & dosagem , Movimentos Oculares/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/administração & dosagem , Reflexo Vestíbulo-Ocular/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Animais , Movimentos Oculares/fisiologia , Feminino , Masculino , Reflexo Vestíbulo-Ocular/fisiologia , Vestíbulo do Labirinto/fisiologia , Xenopus laevis
7.
Restor Neurol Neurosci ; 37(3): 245-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31177251

RESUMO

BACKGROUND: Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. METHODS: The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1-5 and 71-75, and spatial memory (Morris water maze test, MWM) was assessed on days 14-21 and 83-90 after CCI injury or sham surgery. RESULTS: When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. CONCLUSIONS: Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Atividade Motora/efeitos dos fármacos , Degeneração Neural/prevenção & controle , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Memória Espacial/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Masculino , Memantina/administração & dosagem , Ratos , Fatores de Tempo
8.
PLoS One ; 14(5): e0216214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048906

RESUMO

Noisy galvanic vestibular stimulation (nGVS) has been shown to improve dynamic walking stability, affect postural responses, enhance balance in healthy subjects, and influence motor performance in individuals with Parkinson's disease. Although the studies to fully characterize the effect of nGVS are still ongoing, stochastic resonance theory which states that the addition of noisy signal may enhance a weak sensory input signals transmission in a non-linear system may provide a possible explanation for the observed positive effects of nGVS. This study explores the effect of nGVS on fine tracking behavior in healthy subjects. Ten healthy participants performed a computer-based visuomotor task by controlling an object with a joystick to follow an amplitude-modulated signal path while simultaneously receiving a sham or pink noise nGVS. The stimulation was generated to have a zero-mean, linearly detrended 1/f-type power spectrum, Gaussian distribution within 0.1-10 Hz range, and a standard deviation (SD) set to 90% based on each participant's cutaneous threshold value. Results show that simultaneous nGVS delivery statistically improved the tracking performance with a decreased root-mean-squared error of 5.71±6.20% (mean±SD), a decreased time delay of 11.88±9.66% (mean±SD), and an increased signal-to-noise ratio of 2.93% (median, interquartile range (IQR) 3.31%). This study showed evidence that nGVS may be beneficial in improving sensorimotor performance during a fine motor tracking task requiring fine wrist movement in healthy subjects. Further research with a more comprehensive subset of tasks is required to fully characterize the effects of nGVS on fine motor skills.


Assuntos
Estimulação Elétrica/métodos , Destreza Motora/fisiologia , Vestíbulo do Labirinto/patologia , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Ruído , Equilíbrio Postural/fisiologia , Vestíbulo do Labirinto/efeitos dos fármacos , Caminhada/fisiologia
9.
Acta Otolaryngol ; 139(6): 505-510, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30990106

RESUMO

BACKGROUND: Unilateral labyrinthectomy (UL) causes the disappearance of ipsilateral medial vestibular nuclear (ipsi-MVe) activity and induces spontaneous nystagmus (SN), which disappears during the initial process of vestibular compensation (VC). Ipsi-MVe-activity restores in the late process of VC. OBJECTIVE: We evaluated the late process of VC after UL in rats and examined the effects of thioperamide (H3 antagonist) on VC. MATERIALS AND METHODS: MK801 (NMDA antagonist)-induced Fos-like immunoreactive (-LIR) neurons in contra-MVe, which had been suppressed by NMDA-mediated cerebellar inhibition in UL rats was used as an index. RESULTS: The number of MK801-induced Fos-LIR neurons in contra-MVe gradually decreased to the same level as that of sham-operated rats 14 days after UL. Thioperamide moved the disappearance of the MK801-induced Fos-LIR neurons 2 days earlier. The number of MK801-induced Fos-LIR neurons in thioperamide-treated rats was significantly decreased, compared with that of vehicle rats on days 7 and 12 after UL. But, thioperamide did not influence the decline of SN frequency in UL rats. CONCLUSION: These findings suggested that the number of MK801-induced Fos-LIR neurons in contra-MVe was decreased in concordance with the restoration of ipsi-MVe-activity during the late process of VC after UL and that thioperamide accelerated the late, but not the initial process of VC.


Assuntos
Nistagmo Patológico/etiologia , Piperidinas/farmacologia , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/cirurgia , Adaptação Fisiológica , Análise de Variância , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Lateralidade Funcional , Imuno-Histoquímica , Masculino , Nistagmo Patológico/tratamento farmacológico , Nistagmo Patológico/fisiopatologia , Procedimentos Cirúrgicos Otológicos/métodos , Distribuição Aleatória , Ratos , Ratos Wistar , Valores de Referência , Testes de Função Vestibular , Vestíbulo do Labirinto/patologia
10.
J Mol Neurosci ; 67(3): 411-417, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30644035

RESUMO

Although histamine inhibitors have been used in the motility-associated vertigo, the link between histamine and sleep deprivation (SD)-induced vertigo has not been clearly demonstrated. The histamine plasma levels were assayed in the SD volunteers before SD and 24 h after SD. Pinnacle's automated sleep deprivation system was used to establish the female C57BL/6 mice SD model. Histidine decarboxylase inhibitor 4-bromo-3-hydroxybenzoic acid (BHOA), and antihistamine diphenhydramine (DPHM) were injected intraperitoneally to test their effects on SD-induced vertigo. Rotarod tests and vestibular scores 24 and 48 h post SD were utilized to assay the vestibular function. Western blot was used to determine the expression of histidine decarboxylase (HDC) in the vestibular, and PowerChrom was utilized to quantify the concentrations of cerebrospinal fluid (CSF) histamine. SD increased plasma concentration of histamine in humans. Upregulated HDC in the vestibular and increased CSF concentration of histamine can be detected in the SD mice, indicating vestibular dysfunction which can be ameliorated by both BHOA and DPHM. Histamine signaling inhibition may ameliorate SD-induced vertigo, and histamine can be considered as a potential treatment target.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Histidina Descarboxilase/antagonistas & inibidores , Hidroxibenzoatos/farmacologia , Privação do Sono/complicações , Vertigem/tratamento farmacológico , Adulto , Animais , Criança , Inibidores Enzimáticos/farmacologia , Feminino , Histamina/sangue , Histamina/líquido cefalorraquidiano , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Vertigem/etiologia , Vertigem/metabolismo , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/metabolismo
11.
Neurotoxicology ; 71: 75-86, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30578813

RESUMO

Exposure to high levels of bilirubin in hyperbilirubinemia patients and animal models can result in sensorineural deafness. However, the mechanisms underlying bilirubin-induced damage to the inner ear, including the cochlear and vestibular organs, remain unknown. The present analyses of cochlear and vestibular organotypic cultures obtained from postnatal day 3 rats exposed to bilirubin at varying concentrations (0, 10, 50, 100, or 250 µM) for 24 h revealed that auditory nerve fibers (ANFs) and vestibular nerve endings were destroyed even at low doses (10 and 50 µM). Additionally, as the bilirubin dose increased, spiral ganglion neurons (SGNs) and vestibular ganglion neurons (VGNs) exhibited gradual shrinkage in conjunction with nuclei condensation or fragmentation in a dose-dependent manner. The loss of cochlear and vestibular hair cells (HCs) was only evident in explants treated with the highest concentration of bilirubin (250 µM), and bilirubin-induced major apoptosis most likely occurred via the extrinsic apoptotic pathway. Thus, the present results indicate that inner ear neurons and fibers were more sensitive to, and exhibited more severe damage following, bilirubin-induced neurotoxicity than sensory HCs, which illustrates the underlying causes of auditory neuropathy and vestibulopathy in hyperbilirubinemia patients.


Assuntos
Bilirrubina/toxicidade , Neurônios/efeitos dos fármacos , Ototoxicidade/patologia , Gânglio Espiral da Cóclea/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Nervo Coclear/efeitos dos fármacos , Nervo Coclear/patologia , Neurônios/patologia , Técnicas de Cultura de Órgãos , Ratos Sprague-Dawley , Gânglio Espiral da Cóclea/patologia , Nervo Vestibular/efeitos dos fármacos , Nervo Vestibular/patologia , Vestíbulo do Labirinto/patologia
12.
Brain Struct Funct ; 224(2): 613-626, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30460552

RESUMO

Perineuronal nets (PN) restrict neuronal plasticity in the adult brain. We hypothesize that activity-dependent consolidation of PN is required for functional maturation of behavioral circuits. Using the postnatal maturation of brainstem vestibular nucleus (VN) circuits as a model system, we report a neonatal period in which consolidation of central vestibular circuitry for graviception is accompanied by activity-dependent consolidation of chondroitin sulfate (CS)-rich PN around GABAergic neurons in the VN. Postnatal onset of negative geotaxis was used as an indicator for functional maturation of vestibular circuits. Rats display negative geotaxis from postnatal day (P) 9, coinciding with the condensation of CS-rich PN around GABAergic interneurons in the VN. Delaying PN formation, by removal of primordial CS moieties on VN with chondroitinase ABC (ChABC) treatment at P6, postponed emergence of negative geotaxis to P13. Similar postponement was observed following inhibition of GABAergic transmission with bicuculline, in line with the reported role of PN in increasing excitability of parvalbumin neurons. We further reasoned that PN-CS restricts bioavailability of plasticity-inducing factors such as semaphorin 3A (Sema3A) to bring about circuit maturation. Treatment of VN explants with ChABC to liberate PN-bound Sema3A resulted in dendritic growth and arborization, implicating structural plasticity that delays synapse formation. Evidence is thus provided for the role of PN-CS-Sema3A in regulating structural and circuit plasticity at VN interneurons with impacts on the development of graviceptive postural control.


Assuntos
Matriz Extracelular/metabolismo , Rede Nervosa/metabolismo , Reflexo/fisiologia , Semaforina-3A/metabolismo , Vestíbulo do Labirinto/metabolismo , Animais , Condroitina ABC Liase/farmacologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Matriz Extracelular/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Parvalbuminas/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleos Vestibulares/efeitos dos fármacos , Núcleos Vestibulares/metabolismo , Vestíbulo do Labirinto/efeitos dos fármacos
13.
Arch Toxicol ; 93(2): 417-434, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30377733

RESUMO

The cellular and molecular events that precede hair cell (HC) loss in the vestibular epithelium during chronic ototoxic exposure have not been widely studied. To select a study model, we compared the effects of sub-chronic exposure to different concentrations of 3,3'-iminodipropionitrile (IDPN) in the drinking water of two strains of mice and of both sexes. In subsequent experiments, male 129S1/SvImJ mice were exposed to 30 mM IDPN for 5 or 8 weeks; animals were euthanized at the end of the exposure or after a washout period of 13 weeks. In behavioral tests, IDPN mice showed progressive vestibular dysfunction followed by recovery during washout. In severely affected animals, light and electron microscopy observations of the vestibular epithelia revealed HC extrusion towards the endolymphatic cavity. Comparison of functional and ultrastructural data indicated that animals with fully reversible dysfunction did not have significant HC loss or stereociliary damage, but reversible dismantlement of the calyceal junctions that characterize the contact between type I HCs (HCI) and their calyx afferents. Immunofluorescent analysis revealed the loss of calyx junction proteins, Caspr1 and Tenascin-C, during exposure and their recovery during washout. Synaptic uncoupling was also recorded, with loss of pre-synaptic Ribeye and post-synaptic GluA2 puncta, and differential reversibility among the three different kinds of synaptic contacts existing in the epithelium. qRT-PCR analyses demonstrated that some of these changes are at least in part explained by gene expression modifications. We concluded that calyx junction dismantlement and synaptic uncoupling are early events in the mouse vestibular sensory epithelium during sub-chronic IDPN ototoxicity.


Assuntos
Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Vestibulares/efeitos dos fármacos , Nitrilas/toxicidade , Ototoxicidade/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Epitélio/patologia , Epitélio/ultraestrutura , Feminino , Células Ciliadas Auditivas/patologia , Células Ciliadas Vestibulares/metabolismo , Células Ciliadas Vestibulares/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/metabolismo , Ototoxicidade/etiologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Tenascina/metabolismo , Testes de Toxicidade Subcrônica , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/patologia , Vestíbulo do Labirinto/fisiopatologia
14.
Neurotoxicology ; 67: 270-278, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29928918

RESUMO

Chronic occupational exposure to carbon disulfide (CS2) has debilitating motor and sensory effects in humans, which can increase the risk of falls. Although no mention of vestibulotoxic effects is contained in the literature, epidemiological and experimental data suggest that CS2 could cause low-frequency hearing loss when associated with noise exposure. Low-frequency noise might also perturb the peripheral balance receptor through an as-yet unclear mechanism. Here, we studied how exposure to a low-frequency noise combined with 250-ppm CS2 affected balance in rats. Vestibular function was tested based on post-rotary nystagmus recorded by a video-oculography system. These measurements were completed by behavioral tests and analysis of the cerebellum to measure expression levels for gene expression associated with neurotoxicity. Assays were performed prior to and following a 4-week exposure, and again after a 4-week recovery period. Functional measurements were completed by histological analyses of the peripheral organs.Nystagmus was unaltered by exposure to noise alone, while CS2 alone caused a moderate 19% decrease of the saccade number. In contrast, coexposure to 250-ppm CS2 and low-frequency noise decreased both saccade number and duration by 33% and 34%, respectively. After four weeks, recovery was only partial but measures were not significantly different from pre-exposure values. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis of cerebellar tissue revealed a slight but significant modification in expression levels for two genes linked to neurotoxicity in CS2-exposed animals. However, neither histopathological changes to the peripheral receptor nor behavioral differences were observed. Based on all these results, we propose that the effects of CS2 were due to reversible neurochemical disturbance of the efferent pathways managing post-rotatory nystagmus. Because the nervous structures involving the vestibular function appear particularly sensitive to CS2, post-rotary nystagmus could be used as an early, non-invasive measurement to diagnose CS2 intoxication as part of an occupational conservation program.


Assuntos
Estimulação Acústica/efeitos adversos , Dissulfeto de Carbono/toxicidade , Ruído/efeitos adversos , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/fisiologia , Animais , Dissulfeto de Carbono/administração & dosagem , Feminino , Ruído/prevenção & controle , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/prevenção & controle , Ratos , Ratos Long-Evans , Vestíbulo do Labirinto/patologia
15.
Int J Audiol ; 57(sup4): S99-S107, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29741128

RESUMO

OBJECTIVE: The purpose of this article is to discuss the most commonly prescribed vestibulotoxic medications and their impact on the vestibular system, to describe the clinical features of vestibular ototoxicity including symptoms reported by patients, and to describe assessment tools that may be used in a monitoring programme, including the functional impact of vestibular loss. Recently published data from a cohort of patients exposed to systemic aminoglycosides (AGS) are summarised, which highlight the importance of monitoring. The role and importance of vestibular rehabilitation in treating affected individuals is discussed. DESIGN: This is a descriptive article. STUDY SAMPLE: Recently published data from 71 patients with cystic fibrosis with AGS exposure are summarised. RESULTS: Recently published data from a cohort of patients exposed to systemic AGS reveal a high prevalence of vestibular system involvement. CONCLUSIONS: Evidence suggests that including assessment of vestibular function in a programme to monitor for ototoxic damage is essential. While suggestions about possible components of a monitoring programme are made, the need for further study in order to determine an ideal protocol for assessing vestibular system function during and following exposure to toxic agents is stressed.


Assuntos
Aminoglicosídeos/efeitos adversos , Antibacterianos/efeitos adversos , Fibrose Cística/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Doenças Vestibulares/induzido quimicamente , Testes de Função Vestibular , Vestíbulo do Labirinto/efeitos dos fármacos , Fibrose Cística/diagnóstico , Fibrose Cística/microbiologia , Humanos , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/fisiopatologia , Doenças Vestibulares/radioterapia , Vestíbulo do Labirinto/fisiopatologia
16.
J Histochem Cytochem ; 66(11): 801-812, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29762076

RESUMO

Intratympanic gentamicin (ITG) has been used to treat refractory Ménière's disease. Disequilibrium after ITG was still a challenge for some patients, and the underlying mechanism is poorly understood. Our previous study demonstrated that gentamicin distributed in the bilateral vestibular efferent neurons (VEN) after ITG; however, does it lead to VEN damage and cause further disequilibrium in patients following ITG? In this study, we observed severe damaged gentamicin-positive neurons of VEN and severe fractured myelin layer plates around neural fibers when viewed under transmission electron microscopy at day 3 after ITG. At day 30, neurons of VEN presented with relatively normal structures. Compared with the control group, the total number of choline acetyltransferase (CHAT) immunolabeling neurons in bilateral VEN showed a significant decrease both at day 3 and day 30. However, there was no significant difference in the total number of CHAT immunolabeling neurons between day 3 and day 30. It indicates that gentamicin is not only retrogradely transported into bilateral VEN, but also results in the degeneration of VEN after ITG. These findings may be related to patients' disequilibrium symptom after ITG. Furthermore, we speculate that VEN may play a role in vestibular compensation.


Assuntos
Antibacterianos/efeitos adversos , Gentamicinas/efeitos adversos , Doença de Meniere/tratamento farmacológico , Neurônios Eferentes/efeitos dos fármacos , Vestíbulo do Labirinto/citologia , Vestíbulo do Labirinto/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Feminino , Imunofluorescência/métodos , Gentamicinas/administração & dosagem , Cobaias , Imuno-Histoquímica/métodos , Injeção Intratimpânica , Masculino , Doença de Meniere/patologia , Microscopia Eletrônica de Transmissão/métodos , Neurônios Eferentes/patologia , Vestíbulo do Labirinto/inervação , Vestíbulo do Labirinto/patologia
17.
Int J Immunopathol Pharmacol ; 32: 2058738418773833, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734824

RESUMO

It is a well-known fact that inner ear diseases are often caused by microcirculatory disorders, and the recent literature is oriented towards investigations into the relationship between the cardiovascular system and cochleovestibular illness with related classical symptoms: tinnitus, hearing loss, and vertigo or instability. These symptoms, and particularly the vertigo, may be the alarm signal of microcirculatory disorders of the labyrinth or vertebrobasilar circulation so as to represent a possible symptom of posterior circulation stroke. The treatment aimed at correcting the haemodynamic and metabolic imbalance, generated by the cochleovestibular microcirculatory disorders, with drugs that act on the vessel wall being very useful, both alone and in combination with other treatment protocols. This is a multicenter retrospective observational study conducted in 40 neurootological laboratories with 873 patients with cardiovascular risk factors suffering from tinnitus, instability or peripheral vertigo alone or in combination with one another treated for the first time with mesoglycan. The data collected showed that the treatment with mesoglycan, irrespective of the type of vascular risk factor, is not only well tolerated but also significantly and objectively improves the cochleovestibular symptoms and the quality of life of patients suffering from tinnitus, peripheral vertigo and instability.


Assuntos
Cóclea/efeitos dos fármacos , Tontura/tratamento farmacológico , Glicosaminoglicanos/uso terapêutico , Zumbido/tratamento farmacológico , Vertigem/tratamento farmacológico , Vestíbulo do Labirinto/efeitos dos fármacos , Cóclea/fisiopatologia , Tontura/diagnóstico , Tontura/fisiopatologia , Feminino , Glicosaminoglicanos/efeitos adversos , Hemodinâmica/efeitos dos fármacos , Humanos , Itália , Masculino , Microcirculação/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Retrospectivos , Zumbido/diagnóstico , Zumbido/fisiopatologia , Resultado do Tratamento , Vertigem/diagnóstico , Vertigem/fisiopatologia , Vestíbulo do Labirinto/fisiopatologia
18.
Neurotoxicology ; 66: 204-212, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29428870

RESUMO

Physiological methods that can be similarly recorded in humans and animals have a major role in sensory toxicology, as they provide a bridge between human sensory perception data and the molecular and cellular data obtained in animal studies. Vestibular toxicity research lags well behind other sensory systems in many aspects, including the availability of methods for functional assessment in animals that could be robustly translated to human significance. Here we review the methods available for the assessment of vestibular function in both humans and laboratory animals, with an emphasis on their similarity or divergence, to highlight their potential utility for the predictive assessment of vestibular toxicity.


Assuntos
Doenças Vestibulares/induzido quimicamente , Doenças Vestibulares/diagnóstico , Testes de Função Vestibular/métodos , Animais , Humanos , Fenômenos Farmacológicos e Toxicológicos , Especificidade da Espécie , Toxicologia/métodos , Doenças Vestibulares/fisiopatologia , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/fisiopatologia
19.
Hear Res ; 361: 152-156, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29459166

RESUMO

Specific pharmacological blockade of KCNQ (Kv7) channels with XE991 rapidly (within 20 min) and profoundly alters inner ear gravity receptor responses to head motion (Lee et al., 2017). We hypothesized that these effects were attributable to the suppression of K+ secretion following blockade of KCNQ1-KCNE1 channels in vestibular dark cells and marginal cells. To test this hypothesis, K+ secretion was independently inhibited by blocking the Na+-K+-2Cl- cotransporter (NKCC1, Slc12a2) rather than KCNQ1-KCNE1 channels. Acute blockade of NKCC1 with ethacrynic acid (40 mg/kg) eliminated auditory responses (ABRs) within approximately 70 min of injection, but had no effect on vestibular gravity receptor function (VsEPs) over a period of 2 h in the same animals. These findings show that, vestibular gravity receptors are highly resistant to acute disruption of endolymph secretion unlike the auditory system. Based on this we argue that acute suppression of K+ secretion alone does not likely account for the rapid profound effects of XE991 on gravity receptors. Instead the effects of XE991 likely require additional action at KCNQ channels located within the sensory epithelium itself.


Assuntos
Ácido Etacrínico/farmacologia , Gravitação , Movimentos da Cabeça , Canais de Potássio KCNQ/metabolismo , Potássio/metabolismo , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Membro 2 da Família 12 de Carreador de Soluto/efeitos dos fármacos , Vestíbulo do Labirinto/efeitos dos fármacos , Animais , Antracenos/farmacologia , Endolinfa/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Canais de Potássio KCNQ/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Bloqueadores dos Canais de Potássio/farmacologia , Via Secretória , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Fatores de Tempo , Vestíbulo do Labirinto/citologia , Vestíbulo do Labirinto/metabolismo
20.
J Biomed Opt ; 22(8): 1-7, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28853245

RESUMO

Gentamicin, which is still used in modern medicine, is a known vestibular toxic agent, and various degrees of balance problems have been observed after exposure to this pharmacologic agent. Photobiomodulation is a candidate therapy for vertigo due to its ability to reach deep inner ear organs such as the cochlea. Previous reports have suggested that photobiomodulation can improve hearing and cochlea function. However, few studies have examined the effect of photobiomodulation on balance dysfunction. We used a rat model to mimic human vestibulopathy resulting from gentamicin treatment and evaluated the effect of photobiomodulation on vestibular toxicity. Slow harmonic acceleration (SHA) rotating platform testing was used for functional evaluation and both qualitative and quantitative epifluorescence analyses of cupula histopathology were performed. Animals were divided into gentamicin only and gentamicin plus laser treatment groups. Laser treatment was applied to one ear, and function and histopathology were evaluated in both ears. Decreased function was observed in both ears after gentamicin treatment, demonstrated by low gain and no SHA asymmetry. Laser treatment minimized the damage resulting from gentamicin treatment as shown by SHA asymmetry and recovered gain in the treated ear. Histology results reflected the functional results, showing increased hair cell density and epifluorescence intensity in laser-treated cupulae.


Assuntos
Terapia com Luz de Baixa Intensidade/métodos , Vertigem/radioterapia , Neuronite Vestibular/radioterapia , Animais , Antibacterianos/efeitos adversos , Cóclea , Orelha Interna , Gentamicinas/efeitos adversos , Masculino , Ratos , Ratos Sprague-Dawley , Vertigem/etiologia , Neuronite Vestibular/induzido quimicamente , Neuronite Vestibular/complicações , Vestíbulo do Labirinto/efeitos dos fármacos
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