Identification of new pharmacological strategies and mechanisms of action for the therapy of Menière´s disease in vivo.

梅尼埃-S病是第二种常见的外周性前庭眩晕。作为一种可能的病理生理原因，内淋巴积水被讨论。主要症状是反复发作的眩晕、急性听力损失和耳鸣。主要治疗目标是预防这些发作，并因此持续存在听力和前庭缺陷。组胺H1受体激动剂和H3拮抗剂倍他司汀的预防作用已被描述。然而，倍他司汀只是在经验的基础上使用，因为缺少实验数据，甚至是机械性数据。因此，在本项目中，我们的目标是确定治疗梅尼埃S病的新策略和细胞水平上的作用机制。为此，计划用单光子显微技术来研究耳蜗微循环的调节和药物干预的可能性。此外，末端血管的调节应该通过双光子显微镜在细胞水平上进行分析(周细胞和毛细血管纤维细胞内的钙离子，毛细血管渗漏)。功能参数，如听力阈值和前庭诱发肌源性电位，将在慢性积水动物模型的治疗干预后进行进一步分析。考虑到严重的症状和大量的患者，新的治疗方案和对病理生理背景的进一步了解将具有极大的临床和社会经济意义。

Menière´s disease is the second frequent form of peripher vestibular vertigo. As a probable pathophysiological cause an endolymphatic hydrops is discussed. Leading symptoms are recurrent attacks of vertigo, acute hearing loss and tinnitus. Primary treatment goals aim to prevent these attacks and in consequence persisting audiological and vestibular deficits. Prophylactic effects have been described for betahistine a Histamine-H1-receptor-agonist and H3-antagonist. However, betahistine is used only on empirical basis since experimental or even mechanistic data is missing. In the present project we therefore aim to identify new therapeutic strategies for Menière´s disease and mechanisms of action on cellular level. To this end, the regulation of cochlear microcirculation and possibilities of pharmacological interventions are planned to be investigated by 1-photon-intravitalmicroscopy. Furthermore, regulation of terminal vessels is supposed to be analysed on cellular levels by 2-photon-microscopy (intracellular Ca2+ in pericytes and fibrocytes of capillaries, capillary leakage). Functional parameters such as hearing threshold and vestibular evoked myogenic potentials will be further analysed after therapeutic interventions in a chronic hydrops animal model. In regard of the severe symptoms and the large number of patients, new therapeutic options and further insights into the pathophysiological background would be of great clinical and socioeconomic interest.