Effects of Combined Gentamicin and Furosemide Treatment on Cochlear Macrophages

Abstract

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.

Immuno-surveillance and protection of the human cochlea

“…Recently, human studies showed the manifestation of the production of fractalkine gene transcripts in SGNs, spiral lamina regions, and basilar membrane ( 4 ). Macrophage function may depend on the location and differences in macrophage morphology and distribution between the apical and basal regions of the cochlea have been described ( 18 ). It could explain the different vulnerability of the sensory nerves and receptors in the cochlea ( 19 , 20 ).…”