Helling Kai, Wodarzcyk Karl, Brieger Jürgen, Schmidtmann Irene, Li Huige, Mann Wolf J, Heinrich Ulf-Rüdiger
Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, Mainz, Germany.
Auris Nasus Larynx. 2011 Dec;38(6):671-7. doi: 10.1016/j.anl.2011.02.013. Epub 2011 May 26.
Gentamicin application is an important therapeutic option to control vertigo spells in Ménière's disease. However, even in the case of low-dose intratympanic application, gentamicin might contribute to a pathological NO-increase leading to cochlear damage and hearing impairment. The study was performed to evaluate the nitric oxide (NO) reducing capacity of doxycycline in the inner ear after NO-induction by gentamicin.
In a prospective animal study, a single dose of gentamicin (10mg/kg body weight) was injected intratympanically into male guinea pigs (n=48). The auditory brainstem responses (ABRs) were recorded prior to application and 3, 5 and 7 days afterwards. The organ of Corti and the lateral wall of 42 animals were isolated after 7 days and incubated separately for 6h in cell culture medium. Doxycycline was adjusted to organ cultures of 5 animals. Two NOS inhibitors, N(G)-Nitro-l-arginine methyl ester (l-NAME) and NG-monomethyl-l-arginine monoacetate (l-NMMA), were applied in three different concentrations to the organ cultures of 30 animals in total (5 animals per concentration). As controls, seven animals received no further substance except gentamicin. The NO-production was quantified by chemiluminescence. Additional six gentamicin-treated animals were used for immunohistochemical studies.
The ABRs declined continuously from the first to the seventh day after gentamicin application. Doxycycline reduced NO-production in the lateral wall by 54% (p=.029) comparable to the effect of the applied nitric oxide inhibitors. In the organ of Corti, NO-production was reduced by about 41% showing no statistical significance in respect to great inter-animal variations.
The application of doxycycline might offer a new therapeutic approach to prevent NO-induced cochlea damage through ototoxic substances.
庆大霉素应用是控制梅尼埃病眩晕发作的重要治疗选择。然而，即使是低剂量鼓室内应用，庆大霉素也可能导致病理性一氧化氮（NO）增加，进而引起耳蜗损伤和听力损害。本研究旨在评估强力霉素在庆大霉素诱导内耳产生NO后对内耳NO的还原能力。
在一项前瞻性动物研究中，将单剂量庆大霉素（10mg/kg体重）鼓室内注射到雄性豚鼠（n = 48）体内。在给药前以及给药后3、5和7天记录听觉脑干反应（ABR）。7天后分离42只动物的柯蒂氏器和侧壁，并在细胞培养基中分别孵育6小时。对5只动物的器官培养物加入强力霉素。将两种一氧化氮合酶抑制剂，N（G）-硝基-L-精氨酸甲酯（L-NAME）和NG-单甲基-L-精氨酸单乙酸盐（L-NMMA），以三种不同浓度应用于总共30只动物的器官培养物（每种浓度5只动物）。作为对照，7只动物除了接受庆大霉素外未接受其他物质。通过化学发光法定量测定NO的产生。另外6只经庆大霉素处理的动物用于免疫组织化学研究。
庆大霉素给药后第1天至第7天，ABR持续下降。强力霉素使侧壁中NO的产生减少了54%（p = 0.029），与所应用的一氧化氮抑制剂的效果相当。在柯蒂氏器中，NO的产生减少了约41%，由于动物个体差异较大，未显示出统计学意义。
强力霉素的应用可能为预防耳毒性物质引起的NO诱导的耳蜗损伤提供一种新的治疗方法。
