Molecular mechanisms of endolymphatic hydrops and treatments for Meniere's disease

对于包括梅尼埃病在内的内耳疾病患者，通常采用类固醇治疗，但其作用机制尚不清楚。水通道蛋白(AQPs)是一个小的跨膜转运蛋白家族。最近发现，它在调节内耳液的动态平衡方面发挥了作用。为了阐明类固醇在内耳的作用点，我们首先用RT-PCR方法鉴定了大鼠耳蜗中AQP1、2、3、4、5和6mRNAs，以及大鼠内淋巴囊中的AQP1、3、4、5和6mRNAs。然后，我们发现鼓室内注射类固醇以剂量依赖的方式上调大鼠耳蜗水通道蛋白1mRNA的表达。这些结果表明，类固醇可能主要通过AQP1来影响大鼠内耳的水平衡。我们的下一个研究目的是看看内淋巴囊是否真的可以作为一种药物输送系统对内耳器官产生影响。我们采用实时荧光定量聚合酶链式反应的方法，研究了单侧内淋巴囊内注入地塞米松对内耳AQP家族、跨膜水转运体和可能的内淋巴液调节剂基因表达的影响。与对照组相比，只有AQP-3在同侧耳蜗组织中的表达显著上调，且这种上调存在剂量和时间依赖关系。提示内淋巴囊内类固醇可通过前庭导水管调节内耳AQP-3的表达，调节内淋巴液的动态平衡，提示内淋巴囊可能是治疗内耳疾病的窗口。

Steroid treatment for patients with inner ear disorders including Meniere's disease is usually performed, however the mechanism of steroid effects remains to be clarified. The aquaporins (AQPs) are a family of small transmembrane water transporters. It has been recently revealed that it makes a role in regulating homeostasis in the inner ear fluids. To elucidate action points of steroids in the inner ear, we first identified AQP1, 2, 3, 4, 5 and 6 mRNAs in the rat cochlea and AQP1, 3, 4, 5 and 6 in the rat endolymphatic sac by means of RT-PCR. Then, we found that intratympanic injections of steroids upregulated AQP1 mRNA of the rat cochlea in a dose-dependenct manner. These results suggest that steroids may be effective on the water homeostasis in the rat inner ear mainly via AQP1.The next aim of our study is to see if the endolymphatic sac is really available as a drug delivery system to make effects on the inner ear organs. We examined effects of a single insertion of dexamethasone into the rat unilateral endolymphatic sac on mRNA expression of the inner ear AQP family, transmembrane water transporters and putative endolymphatic fluid modulators, by means of real-time quantitative PCR. Only AQP-3 mRNA expression in the ipsilateral cochlea was significantly up-regulated in comparison with controls and the up-regulation was demonstrated both in dose-dependent and time-dependent manners. These findings suggest that the intra-endolymphatic sac steroids could make regulatory effects on the inner ear AQP-3 expression via vestibular aqueduct and modulate the homeostasis of endolymphatic fluids, encouraging the possibility that the endolymphatic sac could be a therapeutic window for the inner ear disease.