Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways.

Cisplatin is an effective chemotherapeutic drug for different cancers, but it also causes severe and permanent hearing loss. Oxidative stress and mitochondrial dysfunction in cochlear hair cells (HCs) have been shown to be important in the pathogenesis of cisplatin-induced hearing loss (CIHL). CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) plays a critical role in mitochondrial oxidative capacity and cellular bioenergetics. Targeting CISD1 may improve mitochondrial function in various diseases. However, the role of CISD1 in cisplatin-induced ototoxicity is unclear. Therefore, this study was performed to assess the role of CISD1 in cisplatin-induced ototoxicity. We found that CISD1 expression was significantly increased after cisplatin treatment in both HEI-OC1 cells and cochlear HCs. Moreover, pharmacological inhibition of CISD1 with NL-1 inhibited cell apoptosis and reduced mitochondrial reactive oxygen species accumulation in HEI-OC1 cells and cochlear explants. Inhibition of CISD1 with small interfering RNA in HEI-OC1 cells had similar protective effects. Furthermore, NL-1 protected against CIHL in adult C57 mice, as evaluated by the auditory brainstem response and immunofluorescent staining. Mechanistically, RNA sequencing revealed that NL-1 attenuated CIHL via the PI3K and MAPK pathways. Most importantly, NL-1 did not interfere with the antitumor efficacy of cisplatin. In conclusion, our study revealed that targeting CISD1 with NL-1 reduced reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis via the PI3K and MAPK pathways in HEI-OC1 cell lines and mouse cochlear explants in vitro, and it protected against CIHL in adult C57 mice. Our study suggests that CISD1 may serve as a novel target for the prevention of CIHL.

AdipoRon reduces cisplatin-induced ototoxicity in hair cells:possible relation to the regulation of mitochondrial biogenesis.

AdipoRon (AR) can exert antidiabetic and anti-inflammatory effects by maintaining mitochondrial structure and function. The present study was designed to explore whether AR protects the auditory cells from cisplatin-induced damage and, if so, to probe the possible mechanisms underlying its action on this type of cells. Cell viability and apoptosis in House Ear Institute-Organization of Corti 1 (HEI-OC1 cells) and mouse cochlea hair cells (HCs) were detected by CCK8 and immunofluorescence. The expressions of apoptosis-related proteins (cleaved caspase-3 and Bcl-2), adiponectin receptor 1 (AdipoR 1) and the key factors relevant to mitochondrial biogenesis（SIRT1 and TFAM）were determined by Western blot and immunofluorescence. Changes in apoptotic rate and expression of SIRT1 and TFAM after silencing of AdipoR 1 (AdipoR 1-siRNA) in HEI-OC1 cells were measured by flow cytometry and Western blot. The levels of reactive oxygen species (ROS) were evaluated by MitoSox red staining. We found that 30 µM cisplatin exposure induced severe cellular damage, which resulted from activation of the mitochondrial apoptotic pathway. Cisplatin decreased the expression of AdipoR 1, SIRT1, and TFAM proteins, leading to impaired mitochondrial biogenesis and increased mitochondrial ROS production. 10 µM AR pre-treatment enhanced mitochondrial biogenesis, decreased mitochondrial ROS levels, alleviated imbalances in the mitochondrial apoptotic pathway, thus reducing cisplatin-induced apoptosis. Taken together, this work reveals that AR exerts anti-apoptotic effects, possibly via regulating mitochondrial biogenesis and function. Interestingly, AR might possess the promising potential to be a novel drug for the prevention and/ or treatment of cisplatin-induced ototoxicity.

Protective role of pyrroloquinoline quinone against gentamicin induced cochlear hair cell ototoxicity.

Gentamicin (GM) is one of the commonly used antibiotics in the aminoglycoside class but is ototoxic, which constantly impacts the quality of human life. Pyrroloquinoline quinone (PQQ) as a redox cofactor produced by bacteria was found in soil and foods that exert an antioxidant and redox modulator. It is well documented that the PQQ can alleviate inflammatory responses and cytotoxicity. However, our understanding of PQQ in ototoxicity remains unclear. We reported that PQQ could protect against GM-induced ototoxicity in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in vitro. To evaluate reactive oxygen species (ROS) production and mitochondrial function, ROS and JC-1 staining, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) measurements in living cells, mitochondrial dynamics analysis was performed. GM-mediated damage was performed by reducing the production of ROS and inhibiting mitochondria biogenesis and dynamics. PQQ ameliorated the cellular oxidative stress and recovered mitochondrial membrane potential, facilitating the recovery of mitochondrial biogenesis and dynamics. Our in vitro findings improve our understanding of the GM-induced ototoxicity with therapeutic implications for PQQ.

Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway.

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.

Prevention and treatment of cisplatin-induced ototoxicity in adults: A systematic review.

OBJECTIVES: Ototoxicity is a common disabling side effect of platinum-based chemotherapy. This study aimed to assess the evidence on the management of platinum-induced ototoxicity in adult cancer patients. METHODS: Four databases were searched up to 1 November 2022. Original studies were included if they reported on a pharmacologic or non-pharmacologic intervention to prevent or treat platinum ototoxicity in adults. The articles' quality was assessed via two grading scales. RESULTS: Nineteen randomised controlled trials and five quasi-experimental studies with 1673 patients were analysed. Eleven interventions were identified, nine pharmacological and two non-pharmacological. Six of the interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins and D-methionine) showed mild benefits in preventing cisplatin-induced ototoxicity. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed with a low risk of bias. The majority of studies inadequately documented intervention-related adverse effects, thereby limiting safety conclusions. CONCLUSIONS: Current interventions have mild benefits in preventing cisplatin-induced ototoxicity in adult cancer patients. Sodium thiosulphate is the most promising intervention as a preventive strategy. Rigorous, high-quality research is warranted, encompassing an evaluation of all potential symptoms and innovative treatment modalities.

Berberine protects against neomycin-induced ototoxicity by reducing ROS generation and activating the PI3K/AKT pathway.

In mammals, aminoglycoside antibiotic-induced injury to hair cells (HCs) and associated spiral ganglion neurons (SGNs) is irreversible and eventually leads to permanent hearing loss. Efforts have been directed towards the advancement of efficacious therapeutic treatments to protect hearing loss, but the ideal substance for treating the damaged cochlear sensory epithelium has yet to be identified. Berberine (BBR), a quaternary ammonium hydroxide extracted from Coptis chinensis, has been found to display potential anti-oxidant and neuroprotective properties. However, its involvement in aminoglycoside antibiotic-induced ototoxicity has yet to be explored or assessed. In the present study, we explored the possible anti-oxidative properties of BBR in mitigating neomycin-triggered ototoxicity. An improved survival of HCs and SGN nerve fibers (NFs) in organ of Corti (OC) explants after neomycin with BBR co-treatment was observed, and BBR treatment attenuated reactive oxygen species (ROS) generation and reduced cleaved caspase-3 signaling by activating six phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling relative subtypes, and the addition of PI3K/AKT suppressor LY294002 resulted in a decrease in the protective effect. The protective effect of BBR against ototoxicity was also evident in a neomycin-injured animal model, as evidenced by the preservation of HC and SGN in mice administered subcutaneous BBR for 7 days. In summary, all results suggest that BBR has potential as a new and effective otoprotective agent, operating via the PI3K/AKT signaling pathway.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) protects hair cells from cisplatin-induced ototoxicity in vitro: possible relation to the activities of p38 MAPK signaling pathway.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) gene encodes rate-limiting enzyme in cholesterol biosynthesis, which is related to cell proliferation and mitochondrial function. The present study was designed to explore the expression of HMGCR in murine cochlear hair cells and HEI-OC1 cells and the possible mechanisms underpinning the actions of HMGCR in cisplatin-induced ototoxicity, with special attention given to p38 mitogen-activated protein kinase (MAPK) activities in vitro. The expressions of HMGCR, p-p38, cleaved caspase-3 and LC3B was measured by immunofluorescence and western blot. JC-1 staining and MitoSOX Red were used to detect mitochondria membrane potential (MMP) and reactive oxygen species (ROS) levels respectively. The apoptosis of auditory cells was assessed by TUNEL staining and flow cytometry. Protein levels of bcl2/bax and beclin1 were examined by western blot. We found that HMGCR was widely expressed in the auditory cells, of both neonatal mice and 2-month-old mice, in cytoplasm, nucleus and stereocilia. Moreover, 30 µM cisplatin elicited the formation of ROS, which, in turn, led to HMGCR reduction, activating p38 kinase-related apoptosis and autophagy in auditory cells. Meanwhile, co-treatment with ROS scavenger at a concentration of 2 mM, N-acetyl-L-cysteine (NAC), could alleviate the aforementioned changes. In addition, HMGCR silencing resulted in higher p38 MAPK-mediated apoptosis and autophagy under cisplatin injury. Taken together, we demonstrate that, for the first time, that HMGCR is expressed in the cochlear. Furthermore, HMGCR exerts protective benefit on auditory cells against cisplatin-mediated injury stimulated by ROS, culminating in regulation of p38 MAPK-dependent apoptosis and autophagy.

Apelin-13 protects against cisplatin-induced ototoxicity by inhibiting apoptosis and regulating STAT1 and STAT3.

The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients' quality of life. This study was designed to investigate the effect of apelin-13 on cisplatin-induced C57BL/6 mice hearing loss model and explore the potential underlying molecular mechanisms. Mice were intraperitoneally injected with 100 µg/kg apelin-13 2 h before 3 mg/kg cisplatin injection for 7 consecutive days. Cochlear explants cultured in vitro were pretreated with 10 nM apelin-13 2 h prior to 30 µM cisplatin treatment for another 24 h. Hearing test and morphology results showed that apelin-13 attenuated cisplatin-induced mice hearing loss and protected cochlear hair cells and spiral ganglion neurons from damage. In vivo and in vitro experimental results showed that apelin-3 reduced cisplatin-induced apoptosis of hair cells and spiral ganglion neurons. In addition, apelin-3 preserved mitochondrial membrane potential and inhibited ROS production in cultured cochlear explants. Mechanistic studies showed that apelin-3 decreased cisplatin-induced cleaved caspase 3 expression but increased Bcl-2; inhibited the expression of pro-inflammatory factors TNF-a and IL-6; and increased STAT1 phosphorylation but decreased STAT3 phosphorylation. In conclusion, our results indicate that apelin-13 could be a potential otoprotective agent to prevent cisplatin-induced ototoxicity by inhibiting apoptosis, ROS production, TNF-α and IL-6 expression, and regulating phosphorylation of STAT1 and STAT3 transcription factors.

Activation of Nrf2 inhibits ferroptosis and protects against oxaliplatin-induced ototoxicity.

Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.

Protective Effects of Infliximab Against Kanamycin-Induced Ototoxicity in Rats.

HYPOTHESIS: To examine the protective effects of infliximab (INF) against kanamycin (KM)-induced hearing loss. BACKGROUND: Tumor necrosis factor α blockers can reduce cellular inflammatory reactions and decrease cell death. METHODS: Thirty-six rats with normal hearing were randomly divided into six groups. The first group was injected with 400 mg/kg KM intramuscularly (IM), the second group with 7 mg/kg INF intraperitoneally (IP) and 400 mg/kg KM IM, the third group with 7 mg/kg INF IP and 200 mg/kg KM IM, and the fourth group with 1 mg/kg 6-methylprednisolone (MP) IP and 400 mg/kg KM IM. Group 5 was injected with 1 mg/kg MP IP and 200 mg/kg KM IM, and group 6 with saline IP once. Auditory brain-stem response (ABR) for hearing thresholds was performed on days 7 and 14. From the frozen sections of the cochlea, the area of the stria vascularis, the number of neurons in the spiral ganglion, the fluorescence intensity of hair cells (FIHC), postsynaptic density (PSD), and presynaptic ribbons (PSRs) were calculated. RESULTS: The KM-induced increase in hearing thresholds was detected on the 14th day. Hearing was only preserved in the group treated with INF after low-dose KM exposure but not in the groups that received high-dose KM. The FIHC, excitatory PSD, and PSR were preserved only in the INF-treated group after half-dose KM exposure. In MP groups, FIHC, excitatory PSD, and PSR were significantly lower than in the control group. CONCLUSIONS: Our results support that tumor necrosis factor-based inflammation may play a role in the ototoxicity mechanism.

Tetramethylpyrazine Attenuates Radiation-Induced Ototoxicity in a Rat Model.

INTRODUCTION: Tetramethylpyrazine (TMP) is a chemical compound, which has been shown to possess numerous biological features such as anticoagulation, inhibition of platelet aggregation, anti-inflammation, capillary dilatation, improvement in microcirculation, and protection against reactive oxygen radicals. The aim of the present study was to investigate the protective effect of TMP against radiation-induced ototoxicity. MATERIALS AND METHODS: 40 rats were divided into four groups. The first group was irradiated for 5 days. The second group received a single dose of 140 mg/kg/day intraperitoneal TMP given to the rats 30 min before radiotherapy (RT) for 5 days. The third group received a single dose of 140 mg/kg/day i.p. TMP for 5 days, whereas the fourth group was administered saline. All rats underwent distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements before and after the application. The temporal bulla of animals was removed for immunohistopathological examination. RESULTS: Signal-noise ratio values were significantly decreased in the RT group for the frequencies of 2-32 kHz after RT (p < 0.05), whereas the difference was not significant in terms of pre- and posttreatment values for the other groups. Also in the RT group, the ABR thresholds were significantly increased after treatment. In H&E staining, the mean scores for outer hair cells (OHCs), stria vascularis (SV), and spiral ganglion (SG) injuries were significantly higher in RT and RT + TMP groups than in the other groups. The mean OHCs and SV injury scores were also significantly higher in the RT group than in the RT + TMP group (p < 0.05). The number of cochleas that showed cytoplasmic caspase-3 immunoreactivity in the OHC, SV, and SG was significantly higher in RT and RT + TMP groups than in the other groups. CONCLUSION: The findings of the present study suggest that TMP may have a therapeutic potential for preventing sensorineural hearing loss (SNHL) related to RT.

Safety of antituberculosis agents used for multidrug-resistant tuberculosis among patients attending the Jamot Hospital of Yaounde, Cameroon.

Background: Recognized in 1994 as a global emergency by the World Health Organization, tuberculosis (TB) remains an ongoing health threat. In Cameroon, the mortality rate is estimated at 2.9%. Treatment of multidrug-resistant TB (MDR-TB) defined as the resistance to the two most effective antiTB drugs, and requires therapy of more than 7 drugs taken on a daily basis during 9-12 months. This study aimed to evaluate the safety profile of treatment regimens used for MDR-TB at Jamot Hospital of Yaounde (JHY). Methods: This was a retrospective cohort study of patients treated for MDR-TB at HJY from January 1, 2017, to December 31, 2019. Patients characteristics of the cohort, drugs regimen were collected and described. All possible adverse drug reactions (ADR) were described clinically and by severity grade. Results: During the study period, 107 patients were included, and 96 (89.7%) experienced at least one ADR. Most parts of the patients (90) experienced mild or moderate ADR. Hearing loss was the most frequent ADR, and led mostly in aminoglycosides dose reduction (n = 30, 96.7%). Gastrointestinal events were commonly observed during the study period. Conclusion: Our findings suggested that ototoxicity was a prominent safety issue during the study period. The implementation of the new short treatment regimen could be effective in reducing the burden of ototoxicity among MDR-TB patients. Nevertheless, new safety issues could emerge.

A Systematic Review of the Chemo/Radioprotective Effects of Melatonin against Ototoxic Adverse Effects Induced by Chemotherapy and Radiotherapy.

BACKGROUND: Although chemotherapy and radiotherapy are effective in cancer treatment, different adverse effects induced by these therapeutic modalities (such as ototoxicity) restrict their clinical use. Co-treatment of melatonin may alleviate the chemotherapy/radiotherapy-induced ototoxicity. OBJECTIVE: In the present study, the otoprotective potentials of melatonin against the ototoxicity induced by chemotherapy and radiotherapy were reviewed. METHODS: According to the PRISMA guideline, a systematic search was carried out to identify all relevant studies on "the role of melatonin against ototoxic damage associated with chemotherapy and radiotherapy" in the different electronic databases up to September 2022. Sixty-seven articles were screened based on a predefined set of inclusion and exclusion criteria. Seven eligible studies were finally included in this review. RESULTS: The in vitro findings showed that cisplatin chemotherapy significantly decreased the auditory cell viability compared to the control group; in contrast, the melatonin co-administration increased the cell viability of cisplatin-treated cells. The results obtained from the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests demonstrated a decreased amplitude of DPOAE and increased values of ABR I-IV interval and ABR threshold in mice/rats receiving radiotherapy and cisplatin; nevertheless, melatonin co-treatment indicated an opposite pattern on these evaluated parameters. It was also found that cisplatin and radiotherapy could significantly induce the histological and biochemical changes in the auditory cells/tissue. However, melatonin co-treatment resulted in alleviating the cisplatin/radiotherapy-induced biochemical and histological changes. CONCLUSION: According to the findings, it was shown that melatonin co-treatment alleviates the ototoxic damage induced by chemotherapy and radiotherapy. Mechanically, melatonin may exert its otoprotective effects via its anti-oxidant, anti-apoptotic, and anti-inflammatory activities and other mechanisms.

Berberine chloride protects cochlear hair cells from aminoglycoside-induced ototoxicity by reducing the accumulation of mitochondrial reactive oxygen species.

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.

DJ-1 Protects auditory cells from cisplatin-induced ototoxicity via regulating apoptosis and autophagy.

AIMS: DJ-1, a multifunctional protein encoded by the Park7 gene, is tightly related to mitochondrial dysfunction, oxidative stress, protein aggregation, and autophagy regulation. The current study was designed to investigate whether DJ-1 is expressed in auditory cells and, if so, to explore the possible correlation between DJ-1 and cisplatin-induced ototoxicity in this type of cells. METHODS: The location and dynamic expression of DJ-1 in mouse cochlea hair cells (HCs) and House Ear Institute-Organ of Corti 1 (HEI-OC1 cells) were detected by immunofluorescence, real-time PCR, and western blot. The apoptosis of auditory cells was assessed by TUNEL staining and flow cytometry. The levels of ROS were evaluated by MitoSox red staining. The expression of protein cleaved caspase-9, cleaved caspase-3, and LC3B was examined by immunofluorescence and western blot. The expressions of certain key factors relevant to apoptosis (Bcl-2 and Bax) and autophagy (Beclin1, p-JNK, and p-c-Jun) were determined by western blot. The dynamic alterations of those factors in response to DJ-1 knockdown in HEI-OC1 cells (DJ-1-KD) were measured by western blot and MitoSox red staining. RESULTS: The expression of DJ-1 was clearly shown in both HCs and HEI-OC1 cells and cisplatin led to the reduction of DJ-1 expression in a concentration and time-dependent manner. Meanwhile, cisplatin-induced apoptotic process was implemented by promoting reactive oxygen species (ROS) production and activating the mitochondrial pathway. Furthermore, DJ-1 explicitly participated in cisplatin-trigged cell damage by regulating autophagy. CONCLUSIONS: Findings from this work clearly reveal, for the first time, that DJ-1 is expressed in the cochlea. Of particular importance, DJ-1 exerts its protective action against cisplatin-elicited injury on auditory cells via regulating apoptosis and autophagy, which provides a new strategy for the prevention of cisplatin-induced ototoxicity.

SIRT3/GLUT4 signaling activation by metformin protect against cisplatin-induced ototoxicity in vitro.

Cisplatin is highly effective for killing tumor cells. However, as one of its side effects, ototoxicity limits the clinical application of cisplatin. The mechanisms of cisplatin-induced ototoxicity have not been fully clarified yet. SIRT3 is a deacetylated protein mainly located in mitochondria, which regulates a variety of physiological processes in cells. The role of SIRT3 in cisplatin-induced hair cell injury has not been founded. In this study, primary cultured cochlear explants exposed to 5 µM cisplatin, as well as OC-1 cells exposed to 10 µM cisplatin, were used to establish models of cisplatin-induced ototoxicity in vitro. We found that when combined with cisplatin, metformin (75 µM) significantly up-regulated the expression of SIRT3 and alleviated cisplatin-induced apoptosis of hair cells. We regulated the expression of SIRT3 to explore the role of SIRT3 in cisplatin-induced auditory hair cell injury. Overexpression of SIRT3 promoted the survival of auditory hair cells and alleviated the apoptosis of auditory hair cells. In contrast, knockdown of SIRT3 impaired the protective effect of metformin and exacerbated cisplatin injury. In addition, we found that the protective effect of SIRT3 may be achieved by regulating GLUT4 translocation and rescuing impaired glucose uptake caused by cisplatin. Our study confirmed that upregulation of SIRT3 may antagonize cisplatin-induced ototoxicity, and provided a new perspective for the study of cisplatin-induced ototoxicity.

The protective effect of aspirin-induced temporary threshold shift in an animal model of cisplatin-related ototoxicity.

PURPOSE: The purpose of this study was to evaluate whether induction of temporary threshold shift (TTS) with aspirin prior to cisplatin exposure can prevent or minimize cisplatin detrimental effects on hearing. METHODS: We randomly divided BALB mice into three groups: (1) cisplatin only, (2) aspirin only, and (3) combined aspirin/cisplatin. Cisplatin was administered as a single intraperitoneal injection of 14 mg/kg. Aspirin was administered for three weeks via intraperitoneal injection of 200 mg/kg sodium salicylate, twice daily. Air conduction thresholds were recorded using Auditory Brainstem Responses (ABR). Cochleae were harvested and cochlear hair cells were counted using a scanning electron microscope (SEM). RESULTS: Aspirin-induced TTS have reached an average of 30.05±16.9 dB after 2 weeks. At 60 days, cisplatin-only treated mice experienced an average threshold shifts of 50.7 dB at 4 kHz, 35.16 dB at 8 kHz, 70 dB at 16 kHz, 53.1 dB at 32 kHz. All threshold shifts were significantly worse than for cisplatin/aspirin treated mice with TTS of 11.85 dB at 4 kHz, 3.58 dB at 8 kHz, 16.58  dB at 16 kHz, 20.41 dB at 32 kHz (p < 0.01). Cochlear cell count with SEM has shown reduction in the number of both inner and outer hair cells in the mid-turn in cisplatin treated mice. CONCLUSION: Aspirin induced TTS can protect from cisplatin-induced ototoxicity. This beneficial effect was demonstrated by auditory thresholds as well as SEM. Larger pre-clinical and clinical studies are still needed to confirm these findings.

Drug Approved to Prevent Cisplatin-Associated Ototoxicity in Children.

Sodium thiosulfate injection (Pedmark) has been approved to decrease the risk of ototoxicity associated with cisplatin use in children who are at least one month old and have localized nonmetastatic solid tumors.Nurses should regularly weigh children taking this drug, as the dose is based on weight. Patients should be premedicated with antiemetics to prevent nausea and vomiting and monitored closely for evidence of electrolyte imbalances.

Protective effects of nigella sativa oil against gentamicin-induced ototoxicity in rats: A dose-ranging study.

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.