聽力損傷是常見的感覺系統障礙之一，耳蝸缺血則是導致聽力損傷的重要因素。因為耳蝸代謝旺盛，需要許多能量來維持正常功能；但其血液供應只來自迷路動脈，易受到影響而造成缺血性病變。已知許多聽力疾患與耳蝸缺血有關，如老化、噪音性聽損等。本論文在於建立一個可逆式耳蝸缺血動物模式，並配合開發耳蝸缺血的體外模式以完整地探討耳蝸缺血時內耳細胞變化，有助於了解耳蝸缺血相關聽力病變之可能機轉，藉此平臺探尋耳蝸缺血與常見耳毒性的交互作用，並進而探尋對缺血性耳蝸病變可能有效的治療方式。
首先完成對天竺鼠迷路動脈解剖構造的探索，並建立耳蝸可逆性缺血的動物模式(第二章)，以及確認天竺鼠迷路動脈暫時性缺血時間與劑量的反應(第三章)。在瞭解動物耳蝸缺氧的組織形態變化後，進而探討動物耳蝸在高壓純氧下的變化(第四章)，以作為未來進一步研究的基礎。在與耳毒性與生物能量的交互作用研究上，首先建立一個動物耳蝸粒線體功能障礙的動物模式，在此模式下顯示耳蝸對醣胺類抗生素的耳毒性會增加(第五章)；最後經由上述建立的動物耳蝸缺血模式，顯示暫時性耳蝸缺血也會明顯增加對醣胺類抗生素的耳毒性，接下來利用HEI-OC1耳蝸細胞株進一步探討缺血與醣胺類抗生素時耳蝸細胞死亡的分子機制(第六章)。最後討論目前對於缺血性耳蝸病變治療策略的研究，並檢討如何應用本模式下探尋可能有助於治療這類疾病的方式，以作為未來臨床應用的基礎(第七章)。
The cochlea is a highly metabolic organ and requires much energy to maintain the normal physiologic function. However, it is an end-artery organ and mainly supplied by the labyrinthine artery, which is a branch of anterior inferior cerebellar artery (AICA). Therefore, the cochlea is sensitive to disturbance of blood flow. Cochlear ischemia has been implicated to be the causative factor in various hearing disorders such as noise induced hearing loss, presbyacusis, or sudden deafness. The first aim of this thesis is to establish an animal model of reversible cochlear ischemia after the detailed exploration of the inner ear circulation. The interaction of aminoglycoside ototoxicity and bioenergetic deficiency of cochlea is then explored. In addition, the in vivo model in coordination with in vitro cochlear ischemia model will provide a new approach to the investigation of the cellular and molecular mechanisms in cochlear ischemia.
In this thesis, the detailed exploration of the inner ear circulation in guinea pigs was completed, followed by the establishment of a reversible cochlear ischemia model in guinea pigs (chapter 2). The time courses and dose responses of cochlear ischemia in guinea pigs were shown in chapter 3. The effects of hyperbaric oxygen on guinea pig cochlea were investigated and demonstrated in chapter 4, which could provide the basis for future researches in therapeutic applications. This thesis also established an animal model of acute cochlear mitochondrial dysfunction to elucidate the interaction of aminoglycoside ototoxicity with bioenergetic deficiency (chapter 5). Increased aminoglycoside ototoxic susceptibility was depicted in the impaired bioenergetic deficiency of acute cochlear mitochondrial dysfunction and ischemia-reperfusion injuries. The molecular mechanisms after the interaction of aminoglycoside and hypoxia/ischemia was investigated via the in vitro model using HEI-OC1 cochlear cell line and described in chapter 6. Finally, previous researches on the therapeutic purposes for cochlear ischemic damage were reviewed in chapter 7. The potential therapeutic opportunities for the ischemia-related hearing losses were raised. By virtue of the in vitro and in vivo model, some evidence-based therapeutic strategies may be identified, which may be useful in clinical applications.
