Study of the protective effect of dexamethasone on cisplatin-induced ototoxicity in rats

Capelo, Isabelle Oliveira Jataí; Batista, Avner Marcos Alves; Brito, Yuri Neyson Ferreira; Diniz, Krissia Braga; Brito, Gerly Anne de Castro; Freitas, Marcos Rabelo de

doi:10.1590/s0102-865020170100000009

Cited by 7 publications

(4 citation statements)

References 29 publications

(32 reference statements)

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“…Previous studies had reported a protective effect of DEX against cisplatin-induced cytotoxicity, while such an effect was not observed in a clinical trial by transtympanic injection.This discrepancy noted between in vitro and clinical studies may be due to the lack of sufficient DEX concentration in the inner ear 26–28. In the present study, we utilized a drug-loaded silk hydrogel as a drug storage system in order to improve the drug concentration in the inner ear.…”

Section: Discussionmentioning

confidence: 99%

<p>Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity</p>

Chen

Liu

et al. 2019

IJN

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Background: Cisplatin is an extensively used anti-neoplastic agent for the treatment of various solid tumors. However, a high incidence of severe ototoxicity is accompanied by its use in the clinic. Currently, no drugs or therapeutic strategies have been approved for the treatment of cisplatin-induced ototoxicity by the FDA. Purpose: The purpose of this study was to investigate the otoprotective effects of dexamethasone (DEX)-loaded silk-polyethylene hydrogel (DEX-SILK) following round window membrane administration in the cisplatin-induced ototoxicity mouse model. Methods: The morphology, gelation kinetics, viscosity and secondary structure of the DEX-SILK hydrogel were analyzed. DEX concentration in the perilymph was tested at different time points following hydrogel injection on the RWM niche. Cultured cells (HEI-OC1), organ of Corti explants (C57/BL6, P0-2), and cisplatin-induced hearing loss mice model (C57/BL6) were used as in vitro and in vivo models for investigating the otoprotective effects of DEX-SILK hydrogel against cisplatin. Results: Encapsulation of DEX with a loading of 8% (w/v) did not significantly change the silk gelation time, and DEX was evenly distributed in the Silk-PEG hydrogel as visualized by scanning electron microscopy (SEM). The concentration of Silk majorly influenced DEX distribution, morphological characteristics, viscosity, and gelation time. The optimized DEX-SILK hydrogel (8% w/v loading, 15% silk concentration, 10 μl) was administered directly onto the RWM of the guinea pigs. The DEX concentration in the perilymph was maintained above 1 μg/ml for at least 21 days for the DEX-SILK, while it was maintained for less than 6 h in the control sample of free DEX. DEX-SILK (5-60 ng/ml) exhibited significant protective effects against cisplatin-induced cellular ototoxicity and notably reduced the production of reactive oxygen species (ROS). Eventually, pretreatment with DEX-SILK effectively preserved outer hair cells in the cultured organ of Corti explants and demonstrated significant hearing protection at 4, 8, and 16 kHz in the cisplatin-induced hearing loss mice as compared to the effects noted following pretreatment with DEX. Conclusion: These results demonstrated the clinical value of DEX-SILK for the therapy of cisplatin-induced ototoxicity.

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Section: Discussionmentioning

confidence: 99%

<p>Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity</p>

Chen

Liu

et al. 2019

IJN

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“…The limiting side effects of its use include nephrotoxicity, neurotoxicity, and ototoxicity (Daldal et al 2007; Rybak et al 2009). Although nephrotoxicity can be controlled and reduced by hydration therapy, no preventive treatments for ototoxicity are currently known (Capelo et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Efficacy of Intratympanic Dexamethasone in Protecting Against Irreversible Hearing Loss in Patients on Cisplatin-Based Cancer Treatment: A Randomized Controlled Phase IIIB Clinical Trial

Moreno

Belinchon

2021

Ear &Amp; Hearing

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Objective: To determine the efficacy of long-term high-dose intratympanic dexamethasone in protecting the hearing capacity of cancer patients undergoing cisplatin-based ototoxic treatment. Design: A randomized controlled phase IIIB clinical trial to evaluate the efficacy of dexamethasone in protecting against hearing loss in patients undergoing cisplatin treatment. The subjects participating in the clinical trial were patients with a neoplastic disease whose treatment protocol included cisplatin. The average dose of cisplatin was 444.87 mg (SD 235.2 mg). Treatment consisted of intratympanically administering dexamethasone via a passive diffusion device called Microwick (8 mg/24 h dose) from the start of treatment with cisplatin to 3 weeks after the last cycle. Patients were administered the medication to one ear, and the contralateral ear was used as the control. The treated ears were randomly chosen using a computer system (randomization). The hearing threshold was evaluated using pure tone audiometry before each cisplatin cycle. Results: Thirty-four patients were recruited over a 2-year period at a reference tertiary hospital, of whom 11 were excluded. Forty-six ears were analyzed (23 treated and 23 control ears). When treatment was completed, the audiometric analysis showed a higher hearing threshold in the study group than in the control group. Differences were statistically significant at frequencies of 500, 1000, and 6000 Hz: 4.9 dB (1.1 to 8.7), 5.5 dB (0.8 to 10.3), and 16 dB (3.2 to 28.7), respectively, (p < 0.05, 95% confidence interval), but were not clinically significant according to the ASHA hearing loss criteria. Both 8.69% infection complications during treatment and 34.8% permanent perforation at 6 mo were detected after device removal. Conclusions: Long-term high-dose intratympanic dexamethasone treatment did not prevent cisplatin-induced hearing loss.

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“…Tested model of acute kidney injury by HS was established according to (Chen et al, 2015b). Doses of Dexa and EGCG were selected as sub-toxic doses, referring to (Capelo et al, 2017) and (Kumaran et al, 2009), respectively.…”

Section: Heat Stress Protocolmentioning

confidence: 99%

Epigallocatechin‐3‐gallate in combination with corticosteroids mitigates heat stress‐induced acute kidney injury through modulating heat shock protein 70 and toll‐like receptor 4‐dependent pathways

Shafeek

El‐Kashef

Abu-Elsaad

et al. 2023

Phytotherapy Research

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Recently, recurrent heat stress (HS) and dehydration have been exhibited to give rise to kidney disease epidemic in hot regions. The current study was carried out to estimate a possible renoprotective effect of dexamethasone (Dexa) and epigallocatechin-3-gallate (EGCG) as a heat shock protein (HSP)-70 inhibitor on HS-induced nephropathy. In total, five groups of rats were used: control group, HS group (exposed to heat for 40 min), Dexa+HS group (rats were injected with Dexa i.p.15 mg/kg/day for 3 days followed by HS), EGCG+HS group (rats received EGCG 100 mg/kg/day, orally, for 7 days followed by HS), and EGCG+ Dexa +HS group (rats received EGCG 100 mg/kg/day, orally, for 7 days and injected Dexa as described along the last 3 days followed by HS). Kidney sections were stained with H&E and scored for tubular injury. A marked increase in creatinine, urea, malondialdehyde (MDA), monocyte chemoattractant protein (MCP)-1, HSP-70, nuclear factor kappa B (NF-κB), toll-like receptor 4 (TLR-4) and Caspase-3 expression was observed after HS induction (p < 0.001). Treatment with EGCG combined with Dexa notably reduced tubular injury, MCP-1, HSP-70, NF-κB, and TLR-4 levels (p < 0.001). Moreover, it increased IL-10, antioxidant capacity and Bcl-2 expression levels in the kidney (p < 0.001). This renoprotective impact might be attributed to anti-inflammatory, antioxidant, and anti-apoptotic mechanisms besides interfering with TLR-4-mediated NF-κB activation pathway.

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Study of the protective effect of dexamethasone on cisplatin-induced ototoxicity in rats

Cited by 7 publications

References 29 publications

<p>Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity</p>

<p>Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity</p>

Evaluating the Efficacy of Intratympanic Dexamethasone in Protecting Against Irreversible Hearing Loss in Patients on Cisplatin-Based Cancer Treatment: A Randomized Controlled Phase IIIB Clinical Trial

Epigallocatechin‐3‐gallate in combination with corticosteroids mitigates heat stress‐induced acute kidney injury through modulating heat shock protein 70 and toll‐like receptor 4‐dependent pathways

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