Abstract:Background: Ototoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy. To date, no FDA approved agents to alleviate or prevent this ototoxicity are available. However, ototoxicity is generally believed to be produced by excessive generation of reactive oxygen species (ROS) in the inner ear, thus leading to the development of various antioxidants, which act as otoprotective agents. Astaxanthin (ATX) is an interesting candidate in the development of new therapies f… Show more
“…Several studies have reported that mechanotransducer (MET) channels mediate the entry of cisplatin into cochlear hair cells, but it remains unclear whether MET channels are blocked during that process. 30,46,53 A study using larval zebrafish confirmed that cisplatin-induced damage to the hair cells relies on functional MET channels. 19 Furthermore, the effect of platinum (II) complexes on adult zebrafish auditory system suggested that cisplatin, and to a limited extent phenanthriplatin, can induce hair cells loss in particular regions of the saccule but not the utricle, 56 suggesting either various regional susceptibility to cisplatin or its distinct diffusion or transport pattern.…”
Section: Discussionmentioning
confidence: 97%
“…Overproduction of ROS can activate the signal transducer and activator of transcription 1 (STAT1), inducing the inflammation. 46 Previous studies have shown that ROS might induce autophagy, which, depending on the stimulation context, can promote either cell survival or lead to cell death. 54,55 The critical step responsible for the ototoxic properties of cisplatin is its transport inside the sensory cell.…”
Section: Discussionmentioning
confidence: 99%
“…28,31 The third otoprotective strategy involves blocking the entry of toxic substances into the inner ear and, in particular, into hair cells. 31,46 Lateral line hair cells share mechanisms of mechanotransduction (MET) with hair cells of the inner ear. 19 Data in the literature suggest that blocking MET channel prevents the intracellular accumulation of cisplatin.…”
Aim: The present review aimed to consolidate and analyze the recent information about the use of zebrafish in studies concerning cisplatin-induced ototoxicity and otoprotection. Material and methods: The PubMed, Web of Science, and Scopus databanks were searched using the following MESH terms: zebrafish, cisplatin, ototoxicity. The identified publications were screened according to inclusion and exclusion criteria and the 26 qualifying manuscripts were included in the full-text analysis. The experimental protocols, including cisplatin concentrations, the exposure duration and the outcome measurements used in zebrafish larvae studies, were evaluated and the reported knowledge was summarized. Results: Twenty-six substances protecting from cisplatin-induced toxicity were identified with the use of zebrafish larvae. These substances include quinine, salvianolic acid B, berbamine 6, benzamil, quercetin, dexmedetomidine, dexamethsanone, quinoxaline, edaravone, apocynin, dimethyl sulfoxide, KR-22335, SRT1720, ORC-13661, 3-MA, D-methionine, mdivi-1, FUT-175, rapamycin, Z-LLF-CHO, ATX, NAC, CYM-5478, CHCP1, CHCP2 and leupeptin. The otoprotective effects of compounds were attributed to their anti-ROS, anti-apoptotic and cisplatin uptake-blocking properties. The broadest range of protection was achieved when the experimental flow used preconditioning with an otoprotective compound and later a co-incubation with cisplatin. Protection against a high concentration of cisplatin was observed only in protocols using short exposure times (4 and 6 h). Conclusions: The data extracted from the selected papers confirm that despite the differences between the human and the zebra fish hearing thresholds (as affected by cisplatin), the sensory cells of zebrafish and larval zebrafish are a valuable tool which could be used: (i) for the discovery of novel otoprotective substances and compounds; (ii) to screen their side effects and (iii) to extend the knowledge on the mechanisms of cisplatin-induced inner ear damage. For future studies, the development of a consensus experimental protocol is highly recommended.
“…Several studies have reported that mechanotransducer (MET) channels mediate the entry of cisplatin into cochlear hair cells, but it remains unclear whether MET channels are blocked during that process. 30,46,53 A study using larval zebrafish confirmed that cisplatin-induced damage to the hair cells relies on functional MET channels. 19 Furthermore, the effect of platinum (II) complexes on adult zebrafish auditory system suggested that cisplatin, and to a limited extent phenanthriplatin, can induce hair cells loss in particular regions of the saccule but not the utricle, 56 suggesting either various regional susceptibility to cisplatin or its distinct diffusion or transport pattern.…”
Section: Discussionmentioning
confidence: 97%
“…Overproduction of ROS can activate the signal transducer and activator of transcription 1 (STAT1), inducing the inflammation. 46 Previous studies have shown that ROS might induce autophagy, which, depending on the stimulation context, can promote either cell survival or lead to cell death. 54,55 The critical step responsible for the ototoxic properties of cisplatin is its transport inside the sensory cell.…”
Section: Discussionmentioning
confidence: 99%
“…28,31 The third otoprotective strategy involves blocking the entry of toxic substances into the inner ear and, in particular, into hair cells. 31,46 Lateral line hair cells share mechanisms of mechanotransduction (MET) with hair cells of the inner ear. 19 Data in the literature suggest that blocking MET channel prevents the intracellular accumulation of cisplatin.…”
Aim: The present review aimed to consolidate and analyze the recent information about the use of zebrafish in studies concerning cisplatin-induced ototoxicity and otoprotection. Material and methods: The PubMed, Web of Science, and Scopus databanks were searched using the following MESH terms: zebrafish, cisplatin, ototoxicity. The identified publications were screened according to inclusion and exclusion criteria and the 26 qualifying manuscripts were included in the full-text analysis. The experimental protocols, including cisplatin concentrations, the exposure duration and the outcome measurements used in zebrafish larvae studies, were evaluated and the reported knowledge was summarized. Results: Twenty-six substances protecting from cisplatin-induced toxicity were identified with the use of zebrafish larvae. These substances include quinine, salvianolic acid B, berbamine 6, benzamil, quercetin, dexmedetomidine, dexamethsanone, quinoxaline, edaravone, apocynin, dimethyl sulfoxide, KR-22335, SRT1720, ORC-13661, 3-MA, D-methionine, mdivi-1, FUT-175, rapamycin, Z-LLF-CHO, ATX, NAC, CYM-5478, CHCP1, CHCP2 and leupeptin. The otoprotective effects of compounds were attributed to their anti-ROS, anti-apoptotic and cisplatin uptake-blocking properties. The broadest range of protection was achieved when the experimental flow used preconditioning with an otoprotective compound and later a co-incubation with cisplatin. Protection against a high concentration of cisplatin was observed only in protocols using short exposure times (4 and 6 h). Conclusions: The data extracted from the selected papers confirm that despite the differences between the human and the zebra fish hearing thresholds (as affected by cisplatin), the sensory cells of zebrafish and larval zebrafish are a valuable tool which could be used: (i) for the discovery of novel otoprotective substances and compounds; (ii) to screen their side effects and (iii) to extend the knowledge on the mechanisms of cisplatin-induced inner ear damage. For future studies, the development of a consensus experimental protocol is highly recommended.
“…Previous studies showed that AST protected against cisplatin-induced hearing loss (CIHL) at high frequencies in rats and neomycin-induced lateral-line HC death in zebra fish 19 , 20 . It is suggested that the antioxidant activity of AST is associated with several potential mechanisms, including the activation of MAPK, nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element (ARE), and PI3K/AKT pathways 21 , 22 , 23 . Figure 1 Molecular docking and dynamic analysis of astaxanthine and KEAP1.…”
Astaxanthine (AST) has important biological activities including antioxidant and anti-inflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss (CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2 (NRF2), was performed and tested
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computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity
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NRF2 mediated pathway using quantitative PCR and Western blotting. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction. Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis
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NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.
“…As per Jiayi Gu et al studies, astaxanthin encapsulated lipid-polymer hybrid nanoparticles have a greater effect against cisplatin-induced toxicity [16]. As per Salam Massadeh et al research, anastrozole was encapsulated by a polyethylene glycolated (PEGylated) polymer-lipid hybrid nanoparticulate device using a direct emulsification solvent evaporation process [17].…”
Polymeric lipid hybrid nanoparticles (PHLNPs) are core-shell nanoparticle structures made up of polymer cores and lipid shells that have properties similar to both polymeric nanoparticles and liposomes. Methotrexate (MTX) loaded PLHNPs containing tween 80, phosphatidylcholine, poly D, L-lactic-co-glycolic acid (PLGA) and glyceryl tripalmitate prepared using solvent injection and homogenisation method for a glioblastoma treatment option. The MTX-loaded PLHNPs optimised by Box-Behnken design to minimise particle size, higher entrapment efficacy and maximise MTX concentration in the brain at 4 h. The particle size, entrapment efficacy, concentration of drug in the brain at 4 h, zeta potential, and AUC (Brain) /AUC (Plasma) ratio were in the range of 173.51-233.37 nm, 70.56-86.34%, 6.38-12.38 lg/mL, 25.78-36.31 mV and 1.02-5.32. In-vitro drug release studies, cellular internalisation of optimised formulation against U-87 MG shows good anticancer effects.
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