“…Post hoc Šídák's multiple comparisons tests identified significant threshold elevation at individual frequencies of 8, 12, and 16 kHz in B6 mice at 15-day posttreatment compared to 2 days posttreatment (5-pointed asterisks in Figure 1A), and significant elevation at 8, 12, 16, and 24 kHz compared to CBA mice at the same time point (6-pointed asterisks in Figure 1A). Although a strain-dependent disparity in ABR thresholds was observed after G/F treatment, it should be noted that the ototoxic challenge induced great inter-animal variation, as reported earlier with other G/F dosing combinations [30]. A characteristic bipolar distribution of ABR thresholds could be seen at each tested frequency 2 days posttreatment, in either strain, when individual threshold values were presented in violin plots (Figure 1B,C).…”
Section: G/f Treatment Induced More Abr Threshold Shift In C57 Bl/6 Micesupporting
confidence: 70%
“…These activated macrophages might linger in the milieu after ototoxic insult and the clearance of damaged tissues, including dead hair cells. Proper manipulation of these macrophages, or associated innate immune responses, could alleviate the inner ear damage due to various environmental insults [12,30]. Conversely, these cells might also interfere with subsequent studies on candidate bioengineering interventions, either neuro-regeneration or cochlear prosthesis.…”
Section: Discussionmentioning
confidence: 99%
“…with a single dose of 400 mg/kg b.w. gentamicin (Sigma-Aldrich, Sigma-Aldrich, St. Louis, MO, USA, G1264, Lot #SLBG7734 V) followed after 3 of 16 30 min by 200 mg/kg b.w. furosemide (Fresenius Kabi, Germany), abbreviated to 400 G/200 F. This dosing combination was selected because it effectively results in cochlear injury in B6 mice with a low mortality rate according to our previous research [12].…”
Section: Mice and Gentamicin/furosemide (G/f) Treatmentmentioning
Combining aminoglycosides and loop diuretics often serves as an effective ototoxic approach to deafen experimental animals. The treatment results in rapid hair cell loss with extended macrophage presence in the cochlea, creating a sterile inflammatory environment. Although the early recruitment of macrophages is typically neuroprotective, the delay in the resolution of macrophage activity can be a complication if the damaged cochlea is used as a model to study subsequent therapeutic strategies. Here, we applied a high dose combination of systemic gentamicin and furosemide in C57 BL/6 and CBA/CaJ mice and studied the ototoxic consequences in the cochlea, including hair cell survival, ribbon synaptic integrity, and macrophage activation up to 15-day posttreatment. The activity of macrophages in the basilar membrane was correlated to the severity of cochlear damage, particularly the hair cell damage. Comparatively, C57 BL/6 cochleae were more vulnerable to the ototoxic challenge with escalated macrophage activation. In addition, the ribbon synaptic deterioration was disproportionately limited when compared to the degree of outer hair cell loss in CBA/CaJ mice. The innate and differential otoprotection in CBA/CaJ mice appears to be associated with the rapid activation of cochlear macrophages and a certain level of synaptogenesis after the combined gentamicin and furosemide treatment.
“…Post hoc Šídák's multiple comparisons tests identified significant threshold elevation at individual frequencies of 8, 12, and 16 kHz in B6 mice at 15-day posttreatment compared to 2 days posttreatment (5-pointed asterisks in Figure 1A), and significant elevation at 8, 12, 16, and 24 kHz compared to CBA mice at the same time point (6-pointed asterisks in Figure 1A). Although a strain-dependent disparity in ABR thresholds was observed after G/F treatment, it should be noted that the ototoxic challenge induced great inter-animal variation, as reported earlier with other G/F dosing combinations [30]. A characteristic bipolar distribution of ABR thresholds could be seen at each tested frequency 2 days posttreatment, in either strain, when individual threshold values were presented in violin plots (Figure 1B,C).…”
Section: G/f Treatment Induced More Abr Threshold Shift In C57 Bl/6 Micesupporting
confidence: 70%
“…These activated macrophages might linger in the milieu after ototoxic insult and the clearance of damaged tissues, including dead hair cells. Proper manipulation of these macrophages, or associated innate immune responses, could alleviate the inner ear damage due to various environmental insults [12,30]. Conversely, these cells might also interfere with subsequent studies on candidate bioengineering interventions, either neuro-regeneration or cochlear prosthesis.…”
Section: Discussionmentioning
confidence: 99%
“…with a single dose of 400 mg/kg b.w. gentamicin (Sigma-Aldrich, Sigma-Aldrich, St. Louis, MO, USA, G1264, Lot #SLBG7734 V) followed after 3 of 16 30 min by 200 mg/kg b.w. furosemide (Fresenius Kabi, Germany), abbreviated to 400 G/200 F. This dosing combination was selected because it effectively results in cochlear injury in B6 mice with a low mortality rate according to our previous research [12].…”
Section: Mice and Gentamicin/furosemide (G/f) Treatmentmentioning
Combining aminoglycosides and loop diuretics often serves as an effective ototoxic approach to deafen experimental animals. The treatment results in rapid hair cell loss with extended macrophage presence in the cochlea, creating a sterile inflammatory environment. Although the early recruitment of macrophages is typically neuroprotective, the delay in the resolution of macrophage activity can be a complication if the damaged cochlea is used as a model to study subsequent therapeutic strategies. Here, we applied a high dose combination of systemic gentamicin and furosemide in C57 BL/6 and CBA/CaJ mice and studied the ototoxic consequences in the cochlea, including hair cell survival, ribbon synaptic integrity, and macrophage activation up to 15-day posttreatment. The activity of macrophages in the basilar membrane was correlated to the severity of cochlear damage, particularly the hair cell damage. Comparatively, C57 BL/6 cochleae were more vulnerable to the ototoxic challenge with escalated macrophage activation. In addition, the ribbon synaptic deterioration was disproportionately limited when compared to the degree of outer hair cell loss in CBA/CaJ mice. The innate and differential otoprotection in CBA/CaJ mice appears to be associated with the rapid activation of cochlear macrophages and a certain level of synaptogenesis after the combined gentamicin and furosemide treatment.
“…Notably, significantly higher ABR thresholds were observed in the KM (200 mg/Kg)-FS (400 mg/Kg) group compared to that in the normal and KM (100 mg/Kg)-FS (200 mg/Kg) groups. To minimize lethality in subsequent experiments, we used doses of KM (200 mg/kg)-FS (400 mg/kg), which have previously been demonstrated to safely create a mouse model of severe ototoxic cochlear damage 16 . Figure 1 ABR thresholds following KM and FS administration experimental protocol.…”
Transforming growth factor-β (TGF-β) signaling plays a significant role in multiple biological processes, including inflammation, immunity, and cell death. However, its specific impact on the cochlea remains unclear. In this study, we aimed to investigate the effects of TGF-β signaling suppression on auditory function and cochlear pathology in mice with kanamycin-induced ototoxicity. Kanamycin and furosemide (KM-FS) were systemically administered to 8-week-old C57/BL6 mice, followed by immediate topical application of a TGF-β receptor inhibitor (TGF-βRI) onto the round window membrane. Results showed significant TGF-β receptor upregulation in spiral ganglion neurons (SGNs) after KM-FA ototoxicity, whereas expression levels in the TGF-βRI treated group remained unchanged. Interestingly, despite no significant change in cochlear TGF-β expression after KM-FS ototoxicity, TGF-βRI treatment resulted in a significant decrease in TGF-β signaling. Regarding auditory function, TGF-βRI treatment offered no therapeutic effects on hearing thresholds and hair cell survival following KM-FS ototoxicity. However, SGN loss and macrophage infiltration were significantly increased with TGF-βRI treatment. These results imply that inhibition of TGF-β signaling after KM-FS ototoxicity promotes cochlear inflammation and SGN degeneration.
“…Previous studies on ototoxicity have mainly focused on ototoxicity-induced hair cell loss and considered neuronal loss to be a secondary consequence caused by loss of trophic support [58][59][60][61][62][63]. However, as in NIHL, direct ototoxicity-induced damage to the synapse and SGNs may occur, as well as ototoxicity-induced swelling of the nerve [64][65][66][67].…”
Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFβ signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation.
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