Otolaryngology, Department of Surgery, University of Melbourne, East Melbourne, 3002, Australia.
Otolaryngology, Department of Surgery, University of Melbourne, East Melbourne, 3002, Australia.
Hear Res. 2018 Oct;368:75-85. doi: 10.1016/j.heares.2018.03.018. Epub 2018 Mar 20.
Local and systemically delivered glucocorticoids are commonly administered to protect the cochlea against damage associated with a variety of insults. There is reason to believe that dexamethasone administered by these routes may arrive at cochlear target sites via different pathways. Clinically, there is a lack of clarity as to which route is more effective in any specific circumstance. This study explores dexamethasone distribution within the guinea pig cochlea following local and systemic delivery methods. A combination of mass spectroscopy and immunohistochemistry were employed to compare both perilymph distribution, tissue uptake and receptor activation. Local administration of dexamethasone to the round window membrane resulted in greater perilymph concentrations, with a basal to apical gradient that favours the cochlear base. Tissue immunofluorescence was intimately related to perilymph concentration following local administration. Systemic administration resulted in much lower perilymph concentrations, with an inverse basal to apical gradient favouring the cochlear apex. Lower perilymph concentrations following systemic administration were associated with minimal tissue immunofluorescence. Despite this, GR activation of the SGNs was equivalent in both administration regimes. These results bring into question the efficacy of measuring perilymph concentrations alone as a surrogacy for dexamethasone distribution and activity in the cochlea, suggesting that the steroid ligand may arrive at its target receptor via alternative pathways. Our results suggest an equivalence in efficacy between local and systemic administration routes early after drug delivery, when the ultimate outcome of GR activation is the goal.
局部和全身给予糖皮质激素通常用于保护耳蜗免受各种损伤的影响。有理由相信，通过这些途径给予的地塞米松可能通过不同的途径到达耳蜗靶位。临床上，对于在任何特定情况下哪种途径更有效还缺乏明确性。本研究探讨了局部和全身给药后地塞米松在豚鼠耳蜗内的分布。结合质谱和免疫组织化学比较了外淋巴液分布、组织摄取和受体激活。局部给予地塞米松至圆窗膜导致外淋巴液浓度更高，具有基底至顶的梯度，有利于耳蜗基底。局部给药后，组织免疫荧光与外淋巴液浓度密切相关。全身给药导致外淋巴液浓度低得多，具有基底至顶的逆梯度，有利于耳蜗顶部。全身给药后外淋巴液浓度较低与组织免疫荧光最小有关。尽管如此，两种给药方案中 SGN 的 GR 激活是等效的。这些结果质疑了单独测量外淋巴液浓度作为地塞米松在耳蜗内分布和活性的替代指标的有效性，表明甾体配体可能通过替代途径到达其靶受体。我们的结果表明，在药物递送后早期，局部和全身给药途径的疗效相当，此时 GR 激活的最终结果是目标。
