The effects of mild hypothermia on the electrode insertion trauma in a murine whole organ cochlea culture

Abstract

IntroductionLocal therapeutic hypothermia (32°C) has been linked experimentally to an otoprotective effect in the electrode insertion trauma. The pathomechanism of the electrode insertion trauma is connected to the activation of apoptosis and necrosis pathways, pro-inflammatory and fibrotic mechanisms. In a whole organ cochlea culture setting the effect of therapeutic hypothermia in an electrode insertion trauma model is evaluated.Material and MethodsThe cochleae of C57Bl6/J mice (Charles River®, Freiburg, Germany) are cultured for 24 hours at 37°C and 32°C after inserting a fishing line through the round window simulating an insertion trauma. The resulting effect was evaluated for the apoptotic reaction – B-cell-Lymphoma-2-Associated-X-Protein (BAX), B-Cell-Lymphoma-2-Protein (BCL2) and Cleaved-Caspase-3 (CC3) –, the inflammatory response – Tumor-Necrosis-Factor-Alpha (TNFα), Interleukin-1-Beta (IL-1Imm) and Cyclooxygenase-2 (COX2) – and proliferation process – Transforming-Growth-Factor-Beta-1 (TGFβ1) – using immunohistochemistry and real-time PCR technique. A minimum of 12 cochlea per experiment were used.ResultsA pro-apoptotic situation was observed in the normothermic group (BAX, CC3 ˃ Bcl2) whereas an anti-apoptotic constellation was found at 32°C culture conditions (BAX, CC3 < Bcl2). Furthermore the effect of the IT knowing to effect the pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression has been reproduced. This reaction was reversed with the application of therapeutic hypothermia resulting in significant lower pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression. TGFβ1 was increased by hypothermia.DiscussionConcluding a protective effect of hypothermia on the experimental electrode insertion trauma can be described by an anti-apoptotic and anti-inflammatory reaction.

Effects of Therapeutic Hypothermia on Macrophages in Mouse Cochlea Explants

“…CD163 is a selective monocyte marker and can be induced by anti-inflammatory stimuli, such as glucocorticosteroids. A similar effect can be expected with the application of hypothermia, another postulated anti-inflammatory stimulus [28][29][30]. With the selection of the CD45 marker, the analysis has been extended to the dendritic cells, another important line of immune cells.…”

“…With the usability of hypothermia in real clinical otologic settings being proven, further information is needed with respect to the underlying pathophysiologic mechanisms associated with electrode insertion trauma. This topic has been elaborated in detail by Schmutzhard et al [30]. The authors utilized a whole-organ cochlea culture model to evaluate the effect of mild hypothermia on electrode insertion trauma.…”

Targeted therapeutic hypothermia protects against noise induced hearing loss

“…Although these studies showed benefits of MTH, systemic application can result in unintended complications and is simply not feasible as a therapeutic application for a global population. Recent studies in cochlear implant trauma ( Tamames et al, 2016 ; Bader et al, 2023 ; Schmutzhard et al, 2023 ) and cisplatin injury ( Spankovich et al, 2016 ; Stanford et al, 2020 ) models provide evidence for localized MTH providing cochlear neuroprotection. Furthermore, several approaches have been proposed to achieve therapeutic levels of hypothermia ( Spankovich et al, 2016 ; Tamames et al, 2016 , 2018 ; Bader et al, 2020 ; Stanford et al, 2020 ; Arteaga et al, 2023 ).…”