However, no differences in intravesicular AG, compared to a control group, were observed until 12 hours after injection [ 90 ]. Myosin7a was hypothesized to play a role in endocytosis-mediated AG uptake due to its concentrated expression at the apical part of hair cells in a region with high amounts of vesicles known as the pericuticular necklace [ 91 , 96 ].
The lack of AG uptake in Myosin7a 6j mutant mice was considered evidence supporting AG toxicity mediated by endocytosis [ 91 ].
Further investigation found that Myosin7a-deficient hair cells exhibit closed MET channels at rest, confounding initial interpretations [ 97 ]. Furthermore, the rate of endocytosis correlates with temperature and, therefore, is decreased in hypothermic conditions [ 98 ].
AG uptake demonstrates little temperature-dependent kinetics, indicating a minor relevance of endocytosis in the process [ 99 ]. Instead, there is strong evidence that AGs enter hair cells through the MET channel located at the top of the stereocilia.
AGs act as open channel blockers of the MET-channel [ , ]. Initially, AGs were not considered to be permeable because diameter estimates of the MET-channel pore were low 0. However, work by Gale and coworkers suggested that larger molecules could pass through the MET channel [ ]. This was quantified by Farris et al.
Marcotti et al. Interestingly, this block was decreased significantly for AG approaching the channel from the internal as opposed to the external face [ 92 ]. As this difference between internal and external blocking of AG makes the MET channel function like a one-way valve, intracellular accumulation of AGs is promoted and might explain the increased susceptibility of hair cells compared to other cell types [ 94 ].
The significance of the MET channel as a major route of AG entry is furthermore supported by the exacerbation of ototoxic damage with noise exposure [ ]. Acoustic stimuli increase the open probability of the MET channel and thereby, increase AG uptake [ ].
Additionally, the distribution of ototoxic damage with increasing hair cell susceptibility from apex to base corresponds to the transduction currents in the cochlea, which are larger in basal than in apical OHCs and, in general, more decreased in inner hair cells IHC [ — ]. Moreover, fluorescently labeled gentamicin has been observed first in the tips of hair cell stereocilia before the fluorescent signal increases in the hair cell body [ 87 ].
Several other ion channels might also contribute to AG uptake into hair cells. It is unclear at this point under what conditions the TRP channels might be open and whether these channels are expressed in the plasma membrane or in other cytosolic compartments. The glycoprotein megalin is another potential mediator for AG uptake. Megalin is predominantly expressed in the proximal tubules of the kidney.
Megalin is capable of binding AGs and is also expressed in the inner ear [ ]. Therefore, it was considered a candidate protein for the uptake of AG into hair cells. However, megalin is a drug receptor engaging in endocytosis and is not expressed in the organ of Corti and sensory hair cells [ — ]. Notwithstanding, megalin has been detected in marginal cells of the stria vascularis, suggesting a role in the transport of AGs into the inner ear fluids [ , ].
Inside the hair cell, AGs cause damage, either directly or indirectly, by first inducing disarray of stereocilia and ultimately ending with apoptotic cell death [ — ].
The presence of AGs within hair cells leads to increased formation of reactive oxygen species ROS or free radicals [ — ]. A common mechanism for the formation of ROS is the Fenton reaction: Here, the presence of iron salts is required [ ]. When gentamicin combines with iron salts, the gentamicin-iron complex enhances iron-catalyzed oxidations and, thereby, directly promotes the formation of ROS [ ].
This requires electrons for which unsaturated fatty acids can act as electron donors. In return, those fatty acids, predominantly arachidonic acid, are oxidized to lipid peroxides [ , ]. As arachidonic acid is an essential fatty acid present in cellular membranes, ROS can affect membrane fluidity and permeability [ , ]. Via lipid peroxidation, ROS can also affect proteins and nucleic acids thereby disrupting the activity of enzymes, ion channels, and receptors [ — ].
ROS naturally occur in the cell as a regular byproduct of cellular metabolism [ — ]. Normally, the cell protects itself from lethal ROS accumulation with intrinsic antioxidants such as glutathione [ , ]. This intrinsic protective system is capable of neutralizing ROS to some extent [ ]. When formation of ROS, however, overwhelms the capacity of these intrinsic protective and repair systems, the cell then undergoes apoptotic cell death [ , ]. The mechanism of involvement of mitochondrial mutations in ototoxic hair cell death is not completely understood.
Exposure to AG leads to impairment of RNA translation and inhibition of protein synthesis within mitochondria [ 65 , 69 , ]. It is further suggested that inhibition of mitochondrial protein synthesis leads to a decrease in ATP [ ]. With the decrease of energy production, the mitochondrial integrity is compromised and predispose to a leakage of cytochrome c and subsequent activation of the apoptotic cascades. Furthermore, it is hypothesized that the mitochondrial RNA mutations when exposed to AG cause an increased formation of ROS, which then promote apoptotic cell death [ ].
Independent extrinsic and intrinsic apoptotic pathways exist [ , ]. The extrinsic pathway is mediated by death receptors including the tumor necrosis factor TNF family.
When stimulated, death receptors activate cysteine-dependent, aspartate-specific proteases also known as caspases. Caspase-8 in turn initiates a cascade involving the activation of caspase-3, caspase-6, and caspase-7, which ultimately execute cellular degeneration [ ]. The intrinsic pathway, in contrast, is the major apoptotic pathway initiated by aminoglycoside ototoxicity Figure 2 [ ].
The intrinsic pathway is predominantly triggered by nonreceptor stimuli such as cytokine deprivation, DNA damage, and cytotoxic stress [ ].
Characteristic for the intrinsic apoptotic pathway is the permeabilization of the outer mitochondrial membrane resulting in leakage of proapoptotic factors from the mitochondrial intermembrane space into the cytoplasm.
Mitochondrial membrane integrity and components of the intrinsic pathway are regulated by proteins of the B-Cell Lymphoma-2 Bcl-2 family [ ]. Bcl-2 is the prototype of this equally named protein family. Studies in other systems report these molecules as key apoptosis mediators, acting upstream of caspase activation [ — ]. The Bcl-2 proteins function as a checkpoint for cell death and survival signals in the mitochondria Figure 2.
The Bcl-2 protein family can be anti- or pro-apoptotic [ , , ]; anti-apoptotic Bcl-2 proteins include Bcl-2 and Bcl-X L [ , ], whereas pro-apoptotic Bcl-2 proteins which promote cell death include Bax, Bak, Bcl-X s , Bid, Bad, and Bim [ , ]. Bcl-2 proteins form hetero- and homodimers within the cell. When a cell is challenged, the balance between anti- and pro-apoptotic Bcl-2 proteins regulate whether or not apoptotic cell death is initiated [ ].
Anti-apoptotic Bcl-2 proteins are able to bind to pro-apoptotic Bcl-2 proteins, thus neutralizing the pro-apoptotic signal [ ]. When the balance moves in favor of apoptosis, the pro-apoptotic cytoplasmic Bcl-2 member Bax translocates to the mitochondria, causing pores in the mitochondrial membrane [ , ]. This leads to loss of mitochondrial transmembrane potential, generation of ROS, and leakage of cytochrome c into the cytoplasm [ , , — ], thus activating the upstream caspase pathway as mentioned above.
Supporting a role of this pathway in the inner ear, hair cell loss, and caspase-9 activation were prevented in utricles from Bcl-2 overexpressing mice when treated with neomycin [ ]. This suggests a role for Bcl-2 in the upstream caspase cascade in aminoglycoside-induced hair cell death.
Another group of mediators of apoptotic hair cell death is the stress-activated protein kinases, including the mitogen-activated protein MAP kinases Figure 2 [ ]. Activation of the JNK signaling pathway appears to precede the release of mitochondrial cytochrome c, which then activates caspases [ , ]. Caspases execute cell death in apoptosis [ ]. The caspase family consists of 14 members in mammals, with only a subset involved in apoptosis [ , ]. Caspases can thus be segregated into upstream and downstream enzymes, which are normally inactive [ , ].
Caspases exist in the cytoplasm normally inactivated by inhibitor of apoptosis proteins IAP [ , ]. Activation of upstream caspases occurs by apoptosis-inducing signals such as p53, which has been shown to activate caspases after administration of cisplatin. Downstream caspases are activated by upstream caspases through cleavage of an inactivating prodomain to produce the mature enzyme [ ].
Caspase-8 is an upstream member that is tightly linked to membrane-associated death domain-containing receptors. When ligands such as Fas ligand or tumor necrosis factor alpha bind to this receptor, caspase-8 is recruited intracellularly, leading to clustering and autoactivation of other caspase-8 molecules [ ]. This subsequently causes activation of downstream caspases such as caspases-3, -6, and Although caspase-8 is detected in HC after AG administration [ , ], it does not play a key role in HC death, as inhibition of this pathway does not prevent HC death or prevent caspase-3 activation [ , , ].
Caspase-9 is an upstream caspase activated by apoptotic signals from the mitochondria. This pathway is initiated by cytochrome c release from mitochondria, which then binds to apoptosis protease activating factor, dATP, in the cytoplasm and procaspase-9 [ , ]. This binding causes cleavage and activation of caspase-9, which subsequently cleaves and activates downstream caspases, ultimately resulting in apoptotic cell death Figure 2.
Activated caspase-9 is detected in cochlear and utricular hair cells after AG treatment in vitro [ , , ]. Caspase-3 is a primary downstream caspase that executes the apoptotic program by cleavage of proteins necessary for cell survival, including Bcl-2, inhibitors of deoxyribonucleases, and cytoskeletal proteins Figure 2 [ — ].
Exposure of mice cochlear cultures to neomycin resulted in apoptotic DNA fragmentation, which could be prevented by a calpain inhibitor [ ]. Overall, apoptotic death of hair cells due to AG exposure is complex and our understanding of it has increased in recent years. A simplified model of the apoptotic cascade in aminoglycoside damaged hair cells is presented in Figure 2 , but it is important to point out that many components of the overall cascade and the interactions among these components are still poorly understood.
This complexity is in part reflected by crosstalks among pathways. Death receptor stimulation, for example, is also capable of activating the intrinsic pathway despite primary involvement in the extrinsic pathway [ ]. With increasing understanding of ototoxic cell death, a myriad of therapeutic efforts have been proposed to target various steps of the complex cascades to hair cell death.
Those strategies include inhibition of apoptosis, neutralization of ROS, and administration of neurotrophic factors. A detailed overview of relevant studies including applied drugs, dosage, and outcome is presented in a table at the end of each subchapter. Caspase inhibitors conferred significant protection against hair cell damage from AG, preserving hair cell morphology as well as function in vitro and in vivo [ , — ] Table 1. Agents targeting upstream stress kinases in the apoptotic cascades also prevented AG-induced hair cell death.
Targeting the Bcl-2 family as the upstream key mediator of apoptosis also prevented AG-induced hair cell loss. Overexpression of the anti-apoptotic Bcl-2 in transgenic mice significantly decreased hair cell loss and preserved hearing function following AG exposure in vitro and in vivo [ , ]. Inoculation of mouse cochlea with an adenovirus vector expressing the anti-apoptotic Bcl-X L before treatment with kanamycin also protected from hair cell loss and preserved hearing function [ ] Table 1.
Another class of stress-activated proteins are the family of heat shock proteins HSPs , which are upregulated in stressed cells in multiple organ systems. HSPs can not only prevent protein aggregation by promoting proper folding of nascent or denaturated polypeptides [ ], but also inhibit apoptosis. Overexpression of HSP in transgenic mice significantly protected from hair cell loss from neomycin treatment in vitro, but also significantly protected from hearing loss and hair cell death in mice injected with kanamycin over the course of 14 days [ , ].
Application of anti-apoptotic agents raises several concerns. The protective results of anti-apoptotic drugs are mainly based on acute studies. Therefore, the sustainability of therapeutic potential and safety remain to be evaluated in chronic exposure scenarios. There is evidence that the protective effects of caspase inhibitors to the inner ear are short term [ ]. Considering that AGs are not metabolized [ 7 , 34 , 73 ] and remain in the hair cells for months [ 88 , ], potential sustainable regimens would conceivably require long-term treatment.
Unfortunately, long-term treatment with anti-apoptotic drugs bears a potential carcinogenic risk, as apoptosis has a crucial primary function in preventing uncontrolled cell proliferation [ ].
This carcinogenic risk, therefore, prohibits potential application in human otologic patients. Whether this risk is decreased over a long period by local application to the inner ear remains to be studied. The therapeutic application of anti-apoptotic agents to rescue hair cells after AG exposure has not been reported, but is of further translational interest.
Aminoglycosides form complexes with iron, thereby, catalyzing the formation of ROS [ ]. Competitive blocking of the Fenton reaction involved by iron chelators, thus, is a reasonable approach to avoid oxidative damage from the beginning.
Therefore, much efforts aiming at prevention of AG-induced hair cell death have focused on iron. Administration of the iron chelators deferoxamine and 2,3-dihydroxybenzoate before AG exposure significantly attenuated hearing threshold shifts and protected from hair cell loss in vivo [ — ]. Acetylsalicylate ASA is another iron chelator with additional direct antioxidant properties. Systemic administration of ASA effectively protects guinea pigs from gentamicin-induced hearing loss [ ].
As ASA is a long-approved and routinely prescribed drug, application in human patients is the logical next step. In randomized, double-blind placebo-controlled studies, ASA significantly protected human patients from ototoxic damage without compromising the antimicrobial efficacy of gentamicin [ — ]. However, ASA itself is ototoxic and potentially causes tinnitus, vertigo, and hearing loss [ ].
Although these symptoms are known to be reversible [ ], AGs remain in hair cells for months [ 88 , ] and ototoxic damage can occur after many years [ 81 ].
In this context, recent studies discovered a decrease of activity in auditory neurons in long-term treatment [ ]. Of further concern is that AGs are frequently prescribed in children and neonates.
N-Acetylcysteine NAC is another drug commonly used in patients. Beside its mucolytic effect, NAC is also a known antioxidant. This observation correlated with lower levels of the intrinsic antioxidant glutathione in basal OHC.
However, survival of basal OHC was significantly improved by cotreatment with NAC as well as glutathione and salicylate [ ]. In hemodialysis patients who received gentamicin treatment for bacteremia, application of NAC resulted in significantly less high frequency hearing threshold shifts compared to a control group receiving gentamicin alone. Treatment with NAC was continued for one week after cessation of the gentamicin therapy and the protective effects persisted after another six weeks [ ].
A myriad of other agents with known antioxidant capacity has been tested for protection and treatment of AG ototoxicity. The hormone melatonin, normally excreted by the pineal gland, also has antioxidant capacity and successfully protected from AG ototoxicity [ , — ]. An alternative protective strategy against AG ototoxicity is the upregulation of intrinsic antioxidant mechanisms such as the superoxide dismutase SOD [ , , ] Table 2.
Overall, antioxidants attenuate ototoxic damage from AGs. However, the majority of antioxidants did not demonstrate complete protection from AG ototoxicity [ — , — , , ] and effects of long-term treatment remain to be studied. There exists a number of alternative approaches to protect against AG ototoxicity. One intriguing approach is moderate exposure to ototoxic stimuli with the intent to increase intrinsic antioxidant mechanisms within the ear.
Exposure to low doses of amikacin or gentamicin for 30 days and consecutive high-dose treatment for another 10 to 12 days resulted in significantly less morphologic and functional hair cell damage [ , ] Table 3. However, this bears the undesirable risk of increased bacterial resistance and, thereby, undermines the primary antimicrobial purpose of the AG application.
Exposure to moderate noise also protects from gentamicin ototoxicity in gerbils [ ] Table 3. As this does not allow for immediate application of AG in therapeutic doses, applicability in human patients appears difficult.
Other studies successfully target NMDA receptors to protect auditory nerves [ , ]. However, the NMDA receptor antagonists dizocilpine and ifenprodil exist as maleate and tartrate salts, which carry intrinsic metal chelating properties [ ].
Their vehicle, dimethyl sulfoxide DMSO , can also act as a radical scavenger [ ]. Therefore, the results of Basile and coworkers [ , ] were challenged by Sha and Schacht [ ]. Nonetheless, NMDA antagonists do interact with receptors of afferent auditory nerve fibers [ ].
Thus, targeting the auditory nerve appears reasonable as AGs interact with certain nerve synapses. AGs can aggravate myasthenia gravis and cause postoperative respiratory suppression suggesting a direct neuromuscular blockade [ — ] Table 3. Presynaptically, AGs interfere with the calcium internalization essential for acetylcholine release [ ]. At the postsynaptic level, streptomycin directly blocks the acetylcholine receptor primarily, whereas neomycin affects the open probability of the ion channel of the acetylcholine receptor [ ].
Also, in rat and mouse cochlear cultures, fluorescently tagged gentamicin accumulates in the afferent auditory nerve fibers in addition to the hair cells [ ]. This direct interaction with the auditory nerve also might explain therapeutic effects by neurotrophic growth factors.
The contribution of neurotrophic growth factors in preventing AG ototoxicity suggests an involvement of the auditory nerve. However, there is evidence that the effects of neurotrophic growth factors are short term. Local application of BDNF Ethacrynic acid EA is a diuretic which increases AG ototoxicity when administered simultaneously [ ]. The authors suggest that EA disrupts the blood-labyrinth barrier, thus creating a gradient promoting efflux of AG from the inner ear fluids back into the bloodstream.
However, the protective effects are time dependent and could not be found when EA was injected 20 hr after the AG [ ]. Moreover, simultaneous AG and EA in patients resulted in ototoxic damage after a single treatment [ ], thereby excluding EA as a treatment option. Overall, prevention of apoptotic hair cell death following AG exposure has been targeted effectively on various levels.
Direct inhibition of apoptotic cascades resulted in functional and morphological preservation of hair cells. Neutralization of free radicals by antioxidants prevented activation of apoptotic enzymes. Furthermore, application of NMDA-receptor antagonists, neurotrophic growth factors, and sound conditioning have prevented ototoxic hair cell damage from AG.
However, these protective results are mainly based on acute studies and the sustainability of therapeutic potential and safety remains to be evaluated in chronic exposure scenarios or in clinical trials.
In light of recent insight and increasing understanding of the mechanisms involved in AG ototoxicity, newer and more effective targets may be revealed in the near future. Those target sites involve the mitochondrial rRNA as well as AG entry into the inner ear fluids and hair cells.
Considering the one-way valve function of the MET channel as a site of AG entry into hair cells [ 92 , 94 ], the prolonged persistence of AG in hair cells poses another obstacle to overcome [ ]. Therefore, avoiding entry of AG into hair cells is potentially promising. The first one involves a reversible block of the MET channel. The process of hearing requires depolarization of the inner hair cell through the MET channel [ , , ].
Blocking of the MET channel would then prevent hair cell depolarization and, therefore pause hearing function. Thus, the MET channel block has to be temporary. MET channel blockers have been tested successfully in vitro [ ]. Yet their in vivo effects are largely unknown.
From electrophysiological measurements, the narrowest part of the MET channel pore has been estimated to be 1. As dihydrostreptomycin is capable of blocking the MET channel [ 92 ], the difference in the dimensions of the MET channel and certain AGs appears to be small. Therefore, widening of the AG diameter by binding of inert molecules on sites irrelevant for antimicrobial activity appears a promising strategy to prohibit passage of AGs through the MET channel into the hair cells.
As the passage through the bacterial membrane is self-promoting and depends on the relative positive charge of the AG [ 42 — 47 , — ], the intended increase of size should not affect bacterial uptake of the AG as long as the polarity and the charge of the new AG molecule remains the same. However, interference with the antimicrobial activity due to sterical impairment of binding to the bacterial ribosome needs to be tested.
Another target lies in preventing AG from entering the inner ear fluids. AGs enter the inner ear fluids through the stria vascularis [ 87 ].
Blocking the passage of AG requires the identification of the transport mechanism in the blood-labyrinth barrier.
AGs are potent antibiotics with limited application due to their side effects. Until the problem of AG ototoxicity is solved, it is crucial to be judicious in prescribing AGs for defined clinical indications.
Furthermore, it is important for clinicians to remember the genetic mutations as a cause for increased susceptibility to ototoxic damage. However, indiscriminate genetic screening is not cost-effective at present.
Instead, a thorough history of the patient and their family regarding ototoxic symptoms from antibiotics helps assessing the individual risk. Independent from genetic mutations, patients should undergo a baseline hearing test including ultrahigh frequencies prior to AG administration to allow for early and unambiguous assessment of potential ototoxic damage. Ricci and A. Huth et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Special Issues. Huth, 1,2 A. Ricci, 1,3 and A. Academic Editor: Jeffrey P. Received 02 Jun Accepted 18 Aug Published 25 Oct Abstract Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Introduction Aminoglycosides AGs are a well-known and successful class of antibiotics.
Pharmacokinetics and Antimicrobial Mechanism of Aminoglycosides The AG class of compounds consists of an aminocyclitol moiety with two or more amino sugar rings [ 29 ]. Ototoxicity and Mechanism of Hair Cell Damage 3. Susceptibility and Genetic Predisposition for Aminoglycoside Ototoxicity While AGs preferentially target the bacterial ribosome, the inner ear and kidney are known to receive collateral damage in many patients receiving treatment [ 11 , 12 ].
Route of Aminoglycosides into Hair Cells After systemic administration, AGs are detected in the cochlea within minutes. Figure 1. Proposed mechanisms of aminoglycoside transport in the inner ear. Figure 2. A simplified schematic of the cell death cascade in hair cells damaged by aminoglycosides. Reactive oxygen species ROS , stress kinases, and the caspase family of proteases are activated and mediate hair cell degeneration caused by aminoglycoside exposure, whereas overexpression of Bcl-2 protects against caspase activation and hair cell loss.
Aminoglycosides damage the mitochondria and can result in generation of ROS and activation of stress kinases. Both ROS and stress kinases can cause cell death directly as well as amplify insults targeting the mitochondria. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family members determines the integrity of the mitochondria.
Cytochrome c leaking out of damaged mitochondria leads to caspase-9 activation, which in turn activates caspase-3 to execute cell death. Streptomycin 1. C, Y local PP i. Table 1. Overview of studies performed to protect from aminoglycoside ototoxicity by inhibition of apoptosis. Table 2. Overview of studies performed to protect from aminoglycoside ototoxicity by antioxidants. Table 3. Overview of studies with alternative strategies to protect from aminoglycoside ototoxicity. References A. Schatz, E.
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A study showed that M, a superoxide dismutase mimetic, prevented gentamicin-induced ototoxicity McFadden et al. Recently, an increasing number of studies have shown that the administration of aminoglycosides leads to JNK activation and apoptosis of vestibular hair cells Figure 2.
Systemic administration of CEP a JNK signal inhibitor attenuates gentamicin-induced hearing loss and hair cell damage Ylikoski et al. Therefore, blocking c-Jun N-terminal kinase can prevent the ototoxicity induced by aminoglycosides.
Figure 2. Aminoglycoside induce activation of JNK and then induces apoptosis. Aminoglycosides enter the outer hair cells, induce the production of ROS. In response to ROS and then activate JNK, they are translocated into the nucleus and activate some genes, which in turn induce mitochondria to release cytochrome c and induce cell apoptosis.
ROS induced by aminoglycosides can cause the release of cytochrome c in mitochondria and cascade activation of caspase, leading to substrate proteolysis and cell collapse. The release of cytochrome c is mediated by B-cell lymphoma-2 Bcl-2 family. Studies have shown that overexpression of Bcl-2 in transgenic mice can reduce hair cell loss and prevent hearing loss after aminoglycosides administration Cunningham et al.
What's more, minocycline attenuate ototoxicity better than the use of caspase inhibitors alone Wei et al. In addition to inhibiting the activation of caspase-3, Minocycline may also inhibit phosphorylation of P38 MAPK and the release of cytochrome c Wei et al. Therefore, it may be more effective to inhibit these ototoxic-inducing pathways together. The above protective agents are based on animal studies and have a preventive effect on ototoxicity.
However, there are some limitations in animal research and there are some problems in the transition from animal research to human clinical research. On the one hand, we need to find suitable protective agents for clinical use, so that the protective agents will not affect the antimicrobial effect of aminoglycosides. Studies have shown that D-methionine does not interfere with antimicrobial effects of tobramycin Fox et al. On the other hand, because of the obvious differences in pharmacokinetics and drug elimination between animals and humans, it is not effective to calculate drug dosage by body weight.
In addition to the above protective agents, aminoglycosides with low ototoxicity such as etimicin can also be used, which can effectively reduce ototoxicity Yao et al. At the same time, new alternative drugs can be developed to reduce ototoxicity. Recent studies have purified hospital gentamicin, and analyzed the ototoxicity and antimicrobial activity of individual C-subtypes and impurities, providing ideas for the design of future drugs O'Sullivan et al.
It has been shown that the use of some antioxidants and inhibitors of caspase can prevent cell apoptosis and effectively prevent aminoglycosides-induced hearing loss. In addition, the delivery of mitochondria-targeted drugs is of great significance for treatment. However, recent reports have found that autophagy may also play an important role in the induction of ototoxicity by aminoglycosides, and autophagy may be protective mechanism of hearing He et al.
Meanwhile, autophagy has been reported to play a role in hearing protection He et al. Autophagy may be another good way to prevent ototoxicity induced by aminoglycosides. The mechanism of ototoxicity induced by aminoglycosides and prevention methods described above have been established from animal experiments and can be used as a potential means to prevent ototoxicity induced by aminoglycosides.
We still have a lot of work to do in the transition from animal research to clinical use. The side effects brought by aminoglycosides to patients should not be ignored, and we should further develop new alternative or therapeutic drugs to treat hearing loss caused by ototoxic drugs.
RC writing-review and editing, funding acquisition, and supervision. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Bared, A.
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