RESUMEN
Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able to protect against manganese-induced ototoxicity. However, the molecular mechanism by which SAL reduces levels of reactive oxygen species (ROS) is unclear. Here, we established an in vitro gentamicin (GM) ototoxicity model to observe the protective effect of SAL on GM-induced hair cells (HC) damage. Cochlear explants of postnatal day 4 rats were obtained and randomly divided into six groups: two model groups (treatment with 0.2 mM or 0.4 mM GM for 24 h); two 400 µmol/L SAL-pretreated groups pretreatment with SAL for 3 h followed by GM treatment (0.2 mM or 0.4 mM) for 24 h; 400 µmol/L SAL group (treatment with SAL for 24 h); control group (normal cultured cochlear explants). The protective effects of SAL on GM-induced HC damage, and on mRNA and protein levels of antioxidant enzymes were observed. HC loss occurred after 24 h of GM treatment. Pretreatment with SAL significantly reduced GM-induced OHC loss. In cochlear tissues, mRNA and protein levels of NRF2 and HO-1 were enhanced in the GM alone group compared with the SAL pretreatment GM treatment group. SAL may protect against GM-induced ototoxicity by regulating the antioxidant defense system of cochlear tissues; SAL can activate NRF2/HO-1 signaling, inhibit NF-κB activation, activate AKT, and increase inhibitory phosphorylation of GSK3ß to decrease GSK3 activity, all of which exert antioxidant effects.
Asunto(s)
Gentamicinas , Glucósidos , Ototoxicidad , Ratas , Animales , Gentamicinas/toxicidad , Gentamicinas/metabolismo , FN-kappa B/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Células Ciliadas Auditivas , Cóclea/metabolismo , Fenoles/farmacología , Fenoles/metabolismo , ARN Mensajero/metabolismoRESUMEN
Environmental pollution poses risks to ecosystems. Among these risks, one finds neurotoxicity and damage to the lateral line structures of fish, such as the neuromast and its hair cells. Zebrafish (Danio rerio) is recommended as model species to be used in ecotoxicological studies and environmental biomonitoring programs aimed at assessing several biomarkers, such as ototoxicity. However, little is known about the history of and knowledge gaps on zebrafish ototoxicity. Thus, the aim of the current study is to review data available in the scientific literature about using zebrafish as animal model to assess neuromast toxicity. It must be done by analyzing the history and publication category, world production, experimental design, developmental stages, chemical classes, neuromasts and hair cell visualization methods, and zebrafish strains. Based on the results, number, survival and fluorescence intensity of neuromasts, and their hair cells, were the parameters oftentimes used to assess ototoxicity in zebrafish. The wild AB strain was the most used one, and it was followed by Tübingen and transgenic strains with GFP markers. DASPEI was the fluorescent dye most often applied as method to visualize neuromasts, and it was followed by Yo-Pro-1 and GFP transgenic lines. Antibiotics, antitumorals, metals, nanoparticles and plant extracts were the most frequent classes of chemicals used in the analyzed studies. Overall, pollutants can harm zebrafish's mechanosensory system, as well as affect their behavior and survival. Results have shown that zebrafish is a suitable model system to assess ototoxicity induced by environmental pollution.
Asunto(s)
Ototoxicidad , Perciformes , Animales , Pez Cebra , Ecosistema , Antibacterianos/toxicidad , Contaminación AmbientalRESUMEN
OBJECTIVE: The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. METHODS: We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. RESULTS: A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. CONCLUSION: This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.
Asunto(s)
Sobrecarga de Hierro , Ototoxicidad , Talasemia beta , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Talasemia beta/complicaciones , Talasemia beta/tratamiento farmacológico , Talasemia beta/epidemiología , Deferasirox/uso terapéutico , Deferiprona/uso terapéutico , Deferoxamina/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/etiología , Estudios de Seguimiento , Estudios Retrospectivos , Ototoxicidad/complicaciones , Ototoxicidad/tratamiento farmacológico , Benzoatos/uso terapéutico , Triazoles/uso terapéutico , Piridonas/uso terapéutico , Quelantes del Hierro/uso terapéutico , Hierro/uso terapéutico , AudiciónRESUMEN
Puerarin (PUE), a flavonoid derivative with vasodilatory effects found in the traditional Chinese medicine kudzu, has anti-sensorineural hearing loss properties. However, the mechanism of its protective effect against ototoxicity is not well understood. In this study, we used in vitro and in vivo methods to investigate the protective mechanism of puerarin against cisplatin (CDDP)-induced ototoxicity. We established an ototoxicity model of CDDP in BALB/c mice and assessed the degree of hearing loss and cochlear cell damage. We used bioinformatics analysis, molecular docking, histological analysis, and biochemical and molecular biology to detect the expression of relevant factors. Our results show that puerarin improved CDDP-induced hearing loss and reduced hair cell loss. It also blocked CDDP-induced activation of TRPV1 and inhibited activation of IP3R1 to prevent intracellular calcium overload. Additionally, puerarin blocked CDDP-stimulated p65 activation, reduced excessive ROS production, and alleviated cochlear cell apoptosis. Our study provides new evidence and potential targets for the protective effect of puerarin against drug-induced hearing loss. Puerarin ameliorates cisplatin-induced ototoxicity and blocks cellular apoptosis by inhibiting CDDP activated TRPV1/IP3R1/p65 pathway, blocking induction of calcium overload and excessive ROS expression.
Asunto(s)
Antineoplásicos , Pérdida Auditiva , Isoflavonas , Ototoxicidad , Animales , Ratones , Antineoplásicos/efectos adversos , Apoptosis , Calcio/metabolismo , Línea Celular , Cisplatino/efectos adversos , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Pérdida Auditiva/metabolismo , Simulación del Acoplamiento Molecular , Especies Reactivas de Oxígeno/metabolismo , Canales Catiónicos TRPV/genéticaRESUMEN
Aminoglycoside, a medicinal category of antibiotics, are used in treatment of Gram-negative bacterial infections. Although they are the most widely-used antibiotics due to their high efficacy and low cost, several main adverse effects have been reported including nephrotoxicity and ototoxicity. Since drug-induced ototoxicity is one of the major etiological causes of acquired hearing loss, we examined cochlear hair cell damages caused by three aminoglycosides (amikacin, kanamycin, and gentamicin), and investigated protective property of an isoquinoline-type alkaloid, Berberine chloride (BC). Berberine, a well-known bioactive compound found from medicinal plants, has been known to have anti-inflammatory, antimicrobial effects. To determine protective effect of BC in aminoglycoside-induced ototoxicity, hair cell damages in aminoglycoside- and/or BC-treated hair cells using ex vivo organotypic culture system of mouse cochlea. Mitochondrial ROS levels and depolarization of mitochondrial membrane potential were analyzed, and TUNEL assay and immunostaining of cleaved caspase-3 were performed to detect apoptosis signals. As the results, it was found that BC significantly prevented aminoglycoside-induced hair cell loss and stereocilia degeneration by inhibiting excessive accumulation of mitochondrial ROS and subsequent loss of mitochondrial membrane potential. It eventually inhibited DNA fragmentation and caspase-3 activation, which were significant for all three aminoglycosides. This study is the first report suggested the preventative effect of BC against aminoglycoside-induced ototoxicity. Our data also suggests a possibility that BC has the potential to exert a protective effect against ototoxicity caused by various ototoxic drugs leading to cellular oxidative stress, not limited to aminoglycoside antibiotics.
Asunto(s)
Berberina , Ototoxicidad , Ratones , Animales , Aminoglicósidos/toxicidad , Aminoglicósidos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Ototoxicidad/metabolismo , Berberina/farmacología , Caspasa 3/genética , Caspasa 3/metabolismo , Cloruros , Antibacterianos/efectos adversos , Células Ciliadas AuditivasRESUMEN
OBJECTIVE: Aminoglycosides are relatively potent antibiotics used against some life-threatening infections but contribute to ototoxicity. Although the beneficial effects of high-dose nigella sativa oil (NSO) on ototoxicity in the form of intratympanic or oral use have been demonstrated, no variable-dose studies have been conducted on this subject. We aimed to investigate the potential protective effect of different doses of intraperitoneal (i.p.) NSO on Gentamicin (GM)-induced ototoxicity with auditory brainstem responses (ABR) testing. METHODS: Thirty adult male Sprague-Dawley rats (300-400 gr) were used in this study. Rats were randomly divided into 5 groups, with six animals in each group: All the groups received GM (120 mg/kg i.p) for ten days. Group 1: 0.9% saline solution (0.3 ml/kg i.p.), Group 2: NSOL (low dose 0.1 ml/kg i.p.), Group 3: NSOM (median dose 0.3 ml/kg i.p.), Group 4: NSOH (high dose 3 ml/kg i.p.), Group 5: NSOML (late onset median dose 0.3 ml/kg i.p) were given for fifteen days. But death occurred in 3 rats in group 4 and they were excluded from the study. The pretreatment and posttreatment ABR testings were performed. RESULTS: The posttreatment ABR results were compared with the pretreatment values. A significant difference was found in group 1 (p:0,002), group 2 (p: 0,040), and group 4 (p: 0,027). When the posttreatment tests were compared with each other, there was a significant difference between groups 1 and 2 (p < 0,001), groups 1 and 3 (p < 0,001), and groups 1 and 5 (p < 0,001). CONCLUSIONS: The administration of 0.1 ml/kg and 3 ml/kg dose of NSO does not prevent ototoxicity. The 0.3 ml/kg dose of NSO effectively prevents GM-induced ototoxicity within both prophylactic and therapeutic use.
Asunto(s)
Gentamicinas , Ototoxicidad , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Gentamicinas/toxicidad , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Aceites de Plantas/farmacología , Antibacterianos/toxicidadRESUMEN
OBJECTIVE: To monitor ototoxicity, air conduction (AC) extended high frequency (EHF) thresholds can be measured up to 16 kHz. However, conductive hearing loss might influence these results. This is unfortunate because the EHF thresholds are important to follow the impact of ototoxic medication during therapy. Therefore a suitable bone conduction (BC) transducer and norm values for EHF BC measurements are needed. DESIGN: In this study three different BC transducers were used: the B71 (Radioear), the KH70 (Präcitronic), and the KLH96 (Westra). Hearing thresholds were measured from 0.125 to 16 kHz using AC transducers (Telephonics TDH39, Sennheiser HDA200), and BC thresholds from 0.25 to 8 kHz with the B71, and from 0.25 to 16 kHz with the KLH96 and KH70. STUDY SAMPLE: 60 ears of 30 normal hearing subjects were measured. RESULTS: The KLH96 showed the highest output for the high frequencies, and distortion measurements were similar to the KH70. The results show that EHF measurements are possible using the KLH96 and KH70 bone conductors. CONCLUSION: EHF BC measurements are reliable when using the KLH96 and KH70 bone conductors. The extended force sensitivity of the used artificial mastoid should be determined for a proper EHF BC calibration.
Asunto(s)
Conducción Ósea , Ototoxicidad , Humanos , Audiometría/métodos , Umbral Auditivo , Calibración , Estimulación Acústica/métodos , Audiometría de Tonos Puros , TransductoresRESUMEN
Cisplatin is a commonly used chemotherapeutic agent that causes debilitating high-frequency hearing loss. No targeted therapies currently exist to treat cisplatin ototoxicity, partly because the underlying mechanisms of cisplatin-induced hair cell damage are not completely defined. Zebrafish may offer key insights to cisplatin ototoxicity because their lateral-line organ contains hair cells that are remarkably similar to those within the cochlea but are optically accessible, permitting observation of cisplatin injury in live intact hair cells. In this study, we used a combination of genetically encoded biosensors in zebrafish larvae and fluorescent indicators to characterize changes in mitochondrial bioenergetics in response to cisplatin. Following exposure to cisplatin, confocal imaging of live intact neuromasts demonstrated increased mitochondrial activity. Staining with fixable fluorescent dyes that accumulate in active mitochondria similarly showed hyperpolarized mitochondrial membrane potential. Zebrafish expressing a calcium indicator within their hair cells revealed elevated levels of mitochondrial calcium immediately following completion of cisplatin treatment. A fluorescent ROS indicator demonstrated that these changes in mitochondrial function were associated with increased oxidative stress. After a period of recovery, cisplatin-exposed zebrafish demonstrated caspase-3-mediated apoptosis. Altogether, these findings suggest that cisplatin acutely disrupts mitochondrial bioenergetics and may play a key role in initiating cisplatin ototoxicity.
Asunto(s)
Cisplatino , Ototoxicidad , Animales , Cisplatino/metabolismo , Pez Cebra , Calcio/metabolismo , Mitocondrias/metabolismo , Apoptosis , Metabolismo EnergéticoRESUMEN
Ototoxicity is one of the main dose-limiting side effects of cisplatin chemotherapy and impairs the quality of life of tumor patients dramatically. Since there is currently no established standard therapy targeting hearing loss in cisplatin treatment, the aim of this study was to investigate the effect of nimodipine and its role in cell survival in cisplatin-associated hearing cell damage. To determine the cytotoxic effect, the cell death rate was measured using undifferentiated and differentiated UB/OC-1 and UB/OC-2 cells, after nimodipine pre-treatment and stress induction by cisplatin. Furthermore, immunoblot analysis and intracellular calcium measurement were performed to investigate anti-apoptotic signaling, which was associated with a reduced cytotoxic effect after nimodipine pre-treatment. Cisplatin's cytotoxic effect was significantly attenuated by nimodipine up to 61%. In addition, nimodipine pre-treatment counteracted the reduction in LIM Domain Only 4 (LMO4) by cisplatin, which was associated with increased activation of Ak strain transforming/protein kinase B (Akt), cAMP response element-binding protein (CREB), and signal transducers and activators of transcription 3 (Stat3). Thus, nimodipine presents a potentially well-tolerated substance against the ototoxicity of cisplatin, which could result in a significant improvement in patients' quality of life.
Asunto(s)
Antineoplásicos , Ototoxicidad , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Apoptosis , Cisplatino/farmacología , Células Ciliadas Auditivas/metabolismo , Humanos , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Nimodipina/farmacología , Calidad de Vida , Regulación hacia ArribaRESUMEN
BACKGROUND: Loop diuretics help to manage the patients with edema associated with congestive heart failure, liver cirrhosis, and renal disease and hypertension. The patients taking loop diuretics may receive other medications to treat comorbidities leading to drug interactions. METHODS: The literature was searched in databases such as Medline/PMC/PubMed, Google Scholar, Cochrane Library, Science Direct, EMBASE, Web of science, Ebsco, Directory of open access journals (DOAJ) and reference lists were used to spot relevant articles using keywords Drug interactions, Pharmacodynamic interactions, Loop diuretics, Bumetanide, Ethacrynic acid, Furosemide, and Torsemide. RESULTS: Loop diuretics are associated with hypokalemia, ototoxicity and other adverse effects. The drugs affected by hypokalemia and having the potential of inducing ototoxicity could interact with loop diuretics pharmacodynamically. Loop diuretics can interact with drugs such as amphotericin B, digoxin, angiotensin-converting enzyme inhibitors (ACE inhibitors), antidiabetic drugs, antifungal agents, dobutamine, gossypoland sotalol due to diuretic associated hypokalemia. In addition, the risk of ototoxicity could be enhanced by the concomitant use of loop diuretics and cisplatin, aminoglycoside antibiotics or phosphodiesterase 5 (PDE 5) inhibitors. Loop diuretics may also interact pharmacodynamically with drugs like cephalosporins, ceritinib, levothyroxine, pixantrone, probenecid, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and herbal drugs. CONCLUSION: Clinicians, pharmacists and other health care providers should take responsibility for the safe use of medications. In addition, they are required to be aware of the drugs interacting with loop diuretics to prevent adverse drug interactions.
Asunto(s)
Hipopotasemia , Ototoxicidad , Interacciones Farmacológicas , Furosemida/farmacología , Furosemida/uso terapéutico , Humanos , Hipopotasemia/inducido químicamente , Hipopotasemia/tratamiento farmacológico , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/efectos adversosRESUMEN
CONTEXT: Presbycusis is age-related, progressive, and symmetrical hearing loss in both ears. Acupuncture can play a vital role in the diagnosis and treatment of deafness, but its functional mechanism is still not entirely clear. OBJECTIVE: The study intended to explore acupuncture's protective effects and mechanism of treatment in addressing ototoxicity induced by gentamicin (GM) in aged mice. DESIGN: The research team designed an animal study, and a mouse model of ototoxicity induced by GM was established. SETTING: The study took place in Nanchong Central Hospital, Sichuan, China. ANIMALS: The animals were 48 male, Kunming mice, with sixteen being three months old and 32 being 18 month old. INTERVENTION: The three-month-old mice were randomly assigned to a control group (n = 8) and a GM group (n = 8). The 18-month-old mice were randomly divided into four groups with eight mice each: a positive control group; a negative control group, the GM group; and two intervention groups, the acupuncture + GM group and the drug + GM group. The GM groups were intraperitoneally injected with 100 mg/kg daily of GM for 10 consecutive days. The acupuncture + GM group received acupuncture, and the drug + GM group was injected intraperitoneally with Genadol. OUTCOME MEASURES: The effects of GM induction and treatment with acupuncture or a drug on the numbers of auditory cochlear hair cells were evaluated via an auditory test and cell staining. A real-time polymerase chain reaction (PCR) was performed for gene detection. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) were measured. RESULTS: The aged mice were susceptible to GM ototoxicity. After acupuncture, the threshold of the auditory brainstem response and the number of cochlear hair cells increased significantly. Acupuncture inhibited oxidative stress via the nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) signaling pathway in the mice. CONCLUSIONS: The data demonstrated that acupuncture can alleviate GM ototoxicity via the NRF2 signaling pathway, providing important support for acupuncture in treatment of GM ototoxicity.
Asunto(s)
Terapia por Acupuntura , Ototoxicidad , Animales , Cóclea , Gentamicinas/toxicidad , Células Ciliadas Auditivas , Masculino , RatonesRESUMEN
Aminoglycosides are widely used antibiotics with notable side effects, such as nephrotoxicity, vestibulotoxicity, and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
Asunto(s)
Aminoglicósidos/efectos adversos , Antibacterianos/efectos adversos , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/genética , Variantes Farmacogenómicas , ARN Ribosómico/genética , Toma de Decisiones Clínicas , Genotipo , Pérdida Auditiva Sensorineural/diagnóstico , Humanos , Ototoxicidad , Seguridad del Paciente , Farmacogenética , Pruebas de Farmacogenómica , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de RiesgoRESUMEN
To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae, selecting for those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits shared structural features and blocked, to varying degrees, the OHC's mechano-electrical transducer (MET) channel, a route of aminoglycoside entry into hair cells. Further characterization of one of the strongest MET channel blockers, UoS-7692, revealed it additionally protected against kanamycin and tobramycin and did not abrogate the bactericidal activity of gentamicin. UoS-7692 behaved, like the aminoglycosides, as a permeant blocker of the MET channel; significantly reduced gentamicin-Texas red loading into OHCs; and preserved lateral-line function in neomycin-treated zebrafish. Transtympanic injection of UoS-7692 protected mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserved hearing. The results confirmed the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides and provide a series of hit compounds that will inform the design of future otoprotectants.
Asunto(s)
Aminoglicósidos/efectos adversos , Cóclea/efectos de los fármacos , Ototoxicidad/prevención & control , Animales , Cóclea/citología , Evaluación Preclínica de Medicamentos/métodos , Embrión no Mamífero/efectos de los fármacos , Femenino , Gentamicinas/efectos adversos , Gentamicinas/farmacología , Células Ciliadas Auditivas/efectos de los fármacos , Masculino , Mecanotransducción Celular/efectos de los fármacos , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Factor de Transcripción Asociado a Microftalmía/genética , Neomicina/efectos adversos , Técnicas de Cultivo de Órganos , Ototoxicidad/etiología , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacología , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
BACKGROUND: Cisplatin-induced ototoxicity is related to oxidative stress. Astaxanthin is one of the most powerful antioxidants in nature. AIMS/OBJECTIVES: To investigate the protective effect of astaxanthin on cisplatin-induced ototoxicity. MATERIALS AND METHODS: Thirty-five Sprague Dawley female rats were divided into 5 groups: control, cisplatin, and cisplatin with 10, 20, and 40 mg/kg astaxanthin groups. Cisplatin group received a single intraperitoneal injection of 14 mg/kg cisplatin. While saline was administered in the control group, in the other 3 groups, 10, 20, and 40 mg/kg daily doses of astaxanthin were administered through orogastric cannula before administration of cisplatin. Baseline and 10th day otoacoustic emission tests were administered. An intracardiac blood sample was taken to measure total antioxidant capacity (TAC), and the cochleas of the animals were investigated histopathologically. RESULTS: Hearing level of astaxanthin 40 mg/kg + cisplatin group was higher at 24 kHz and 32 kHz frequencies compared to the cisplatin group. The TAC value of the cisplatin group was lower than both the control and astaxanthin + cisplatin groups (P < .05). On histopathological examination, the other groups were deformed compared to the control group, but no statistically significant difference was observed between the astaxanthin + cisplatin and cisplatin groups. CONCLUSIONS AND SIGNIFICANCE: Astaxanthin showed protective effect at high frequencies when it was administered at high dose. Thus, astaxanthin may have protective effect against cisplatin-induced ototoxicity.
Asunto(s)
Antioxidantes/farmacología , Cisplatino/efectos adversos , Ototoxicidad/prevención & control , Sustancias Protectoras/farmacología , Animales , Cóclea/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Emisiones Otoacústicas Espontáneas , Ototoxicidad/etiología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Xantófilas/farmacologíaRESUMEN
OBJECTIVES: The objective of this study was to investigate the potential protective effect of Nigella sativa oil (NSO) against cis-diamminedichloroplatinum or cisplatin (CDDP)-induced ototoxicity. MATERIALS AND METHODS: Twenty-four Wistar albino rats were randomly and equally divided into four groups. Groups 1 and 2 were given a total of 15 mg/kg CDDP intraperitoneally, which was divided equally into three doses on days 1, 3, and 5. Group 2 was treated via gavage feeding with 15 ml NSO that was divided into five doses on days 1, 3, 5, 7, and 9. Groups 3 and 4 received only 15 ml of NSO and 15 ml of 0.9% saline solution, respectively, which were orally administered and divided into five doses on days 1, 3, 5, 7, and 9. Baseline high-frequency (8, 12, 16, and 32 kHz) auditory brainstem response (ABR) measurements were collected in all the groups before the medical administrations and were repeated on the 14th day before sacrifice. Afterward, a histopathological evaluation of the cochlea was performed. RESULTS: There was a significant difference in the histopathological changes between group 1 and the other groups (p<0.01). Changes in the spiral ganglion cells, the stria vascularis, and the external ciliated cells were significantly different between groups 1 and 2 (p=0.019, 0.039, and 0.045, respectively). The ABR results revealed significant differences in the 16 and 32 kHz measurements between groups 1 and 2 (p=0.013 and p<0.01, respectively). CONCLUSION: According to the results, NSO may have a protective effect on cochlear function against the disruptive effects of CDDP in rats.
Asunto(s)
Antineoplásicos , Ototoxicidad , Animales , Cisplatino , Aceites de Plantas , Ratas , Ratas WistarRESUMEN
Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.
Asunto(s)
Antineoplásicos , Ácidos Grasos Omega-3 , Ototoxicidad , Antineoplásicos/toxicidad , Carboplatino , Cisplatino/toxicidad , Humanos , Estrés Oxidativo , Platino (Metal)/toxicidadRESUMEN
Despite the excellent antimicrobial activity of aminoglycoside antibiotics, permanent inner ear damage associated with the use of these drugs has resulted in the need to develop strategies to address the ototoxic risk given their widespread use. In a previous study, we showed that avocado oil protects ear hair cells from damage caused by neomycin. However, the detailed mechanism by which this protection occurs is still unclear. Here, we investigated the auditory cell-protective mechanism of enhanced functional avocado oil extract (DKB122). RNA sequencing followed by pathway analysis revealed that DKB122 has the potential to enhance the expression of detoxification and antioxidant genes associated with glutathione metabolism (Hmox4, Gsta4, Mgst1, and Abcc3) in HEI-OC1 cells. Additionally, DKB122 effectively decreased ROS levels, resulting in the inhibition of apoptosis in HEI-OC1 cells. The expression of the inflammatory genes that encode chemokines and interleukins was also downregulated by DKB122 treatment. Consistent with these results, DKB122 significantly inhibited p65 nuclear migration induced by TNF-α or LPS in HEI-OC1 cells and THP-1 cells and the expression of inflammatory chemokine and interleukin genes induced by TNF-α was significantly reduced. Moreover, DKB122 treatment increased LC3-II and decreased p62 in HEI-OC1 cells, suggesting that DKB122 increases autophagic flux. These results suggest that DKB122 has otoprotective effects attributable to its antioxidant activity, induction of antioxidant gene expression, anti-inflammatory activity, and autophagy activation.
Asunto(s)
Aminoglicósidos/efectos adversos , Antibacterianos/efectos adversos , Ototoxicidad/tratamiento farmacológico , Ototoxicidad/etiología , Ototoxicidad/genética , Persea/química , Aceites de Plantas/farmacología , Aceites de Plantas/uso terapéutico , Autofagia/efectos de los fármacos , Autofagia/genética , Células Cultivadas , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Células Ciliadas Auditivas Internas/efectos de los fármacos , Células Ciliadas Auditivas Internas/patología , Humanos , Mediadores de Inflamación/metabolismo , Fase I de la Desintoxicación Metabólica/genética , Ototoxicidad/patología , Estrés Oxidativo/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell line, A549, to determine the effects of the curcuminoids and cisplatin on cell viability and several apoptotic signaling mechanisms. Cellular viability was measured using the MTT assay. A scratch assay was used to measure cell migration and fluorescent spectrophotometry to measure reactive oxygen species (ROS) production. Western blots and luminescence assays were used to measure the expression and activity of apoptosis-inducing factor (AIF), caspases-3/7, -8, -9, and -12, c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and proto-oncogene tyrosine-protein kinase (Src). A zebrafish model was used to evaluate auditory effects. Cisplatin, the curcuminoids, and their combinations had similar effects on cell viability (IC50 values: 2-16 µM) and AIF, caspase-12, JNK, MAPK, and Src expression, while caspase-3/7, -8, and -9 activity was unchanged or decreased. Cisplatin increased ROS yield (1.2-fold), and curcuminoid and combination treatments reduced ROS (0.75-0.85-fold). Combination treatments reduced A549 migration (0.51-0.53-fold). Both curcuminoids reduced auditory threshold shifts induced by cisplatin. In summary, cisplatin and the curcuminoids might cause cell death through AIF and caspase-12. The curcuminoids may potentiate cisplatin's effect against A549 migration, but may counteract cisplatin's effect to increase ROS production. The curcuminoids might also prevent cisplatin ototoxicity.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos de Bencilideno/uso terapéutico , Cisplatino/efectos adversos , Diarilheptanoides/uso terapéutico , Ototoxicidad/tratamiento farmacológico , Piperidonas/uso terapéutico , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Bencilideno/química , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Cisplatino/química , Diarilheptanoides/química , Diarilheptanoides/farmacología , Potenciales Evocados Auditivos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ototoxicidad/fisiopatología , Piperidonas/química , Proto-Oncogenes Mas , Pez CebraRESUMEN
Individuals treated for multidrug-resistant tuberculosis (MDR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss. However, AG ototoxicity has never been conceptually integrated or causally linked to MDR-TB patients' pre-treatment health condition. We sought to develop a framework that examines the relationships between pre-treatment conditions and AG-induced hearing loss among MDR-TB-infected individuals in sub-Saharan Africa. The adverse outcome pathway (AOP) approach was used to develop a framework linking key events (KEs) within a biological pathway that results in adverse outcomes (AO), which are associated with chemical perturbation of a molecular initiating event (MIE). This AOP describes pathways initiating from AG accumulation in hair cells, sound transducers of the inner ear immediately after AG administration. After administration, the drug catalyzes cellular oxidative stress due to overproduction of reactive oxygen species. Since oxidative stress inhibits mitochondrial protein synthesis, hair cells undergo apoptotic cell death, resulting in irreversible hearing loss (AO). We identified the following pre-treatment conditions that worsen the causal linkage between MIE and AO: HIV, malnutrition, aging, noise, smoking, and alcohol use. The KEs are: (1) nephrotoxicity, pre-existing hearing loss, and hypoalbuminemia that catalyzes AG accumulation; (2) immunodeficiency and antioxidant deficiency that trigger oxidative stress pathways; and (3) co-administration of mitochondrial toxic drugs that hinder mitochondrial protein synthesis, causing apoptosis. This AOP clearly warrants the development of personalized interventions for patients undergoing MDR-TB treatment. Such interventions (i.e., choosing less ototoxic drugs, scheduling frequent monitoring, modifying nutritional status, avoiding poly-pharmacy) will be required to limit the burden of AG ototoxicity.
Asunto(s)
Aminoglicósidos/efectos adversos , Antituberculosos/efectos adversos , Ototoxicidad/etiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Rutas de Resultados Adversos , África del Sur del Sahara , Aminoglicósidos/administración & dosificación , Antituberculosos/administración & dosificación , Apoptosis/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/fisiopatología , Humanos , Ototoxicidad/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Auditory-nerve fibers are lost steadily with age and as a possible consequence of noise-induced glutamate excitotoxicity. Auditory-nerve loss in the absence of other cochlear pathologies is thought to be undetectable with a pure-tone audiogram while degrading real-world speech perception (hidden hearing loss). Perceptual deficits remain unclear, however, due in part to the limited behavioral capacity of existing rodent models to discriminate complex sounds. The budgerigar is an avian vocal learner with human-like behavioral sensitivity to many simple and complex sounds and the capacity to mimic speech. Previous studies in this species show that intracochlear kainic-acid infusion reduces wave 1 of the auditory brainstem response by 40-70%, consistent with substantial excitotoxic auditory-nerve damage. The present study used operant-conditioning procedures in trained budgerigars to quantify kainic-acid effects on tone detection across frequency (0.25-8â¯kHz; the audiogram) and as a function of duration (20-160â¯ms; temporal integration). Tone thresholds in control animals were lowest from 1 to 4â¯kHz and decreased with increasing duration as in previous studies of the budgerigar. Behavioral results in kainic-acid-exposed animals were as sensitive as in controls, suggesting preservation of the audiogram and temporal integration despite auditory-nerve loss associated with up to 70% wave 1 reduction. Distortion-product otoacoustic emissions were also preserved in kainic-acid exposed animals, consistent with normal hair-cell function. These results highlight considerable perceptual resistance of tone-detection performance with selective auditory-nerve loss. Future behavioral studies in budgerigars with auditory-nerve damage can use complex speech-like stimuli to help clarify aspects of auditory perception impacted by this common cochlear pathology.