水杨酸(阿司匹林)具有良好的抗炎作用，但耳毒性等副作用限制了其应用范围。近期临床研究发现，长期大剂量使用水杨酸可导致永久性耳聋，基础实验也证实水杨酸不可逆性诱发螺旋神经节细胞（SGN）凋亡，但机制不明。已知水杨酸通过抑制环氧化酶（COX）发挥药理作用，并可同时抑制COX-1和COX-2两种亚型，但尚不明确何种途径是耳毒性的主因。COX-1、COX-2在耳蜗中广泛表达，并在其它原因导致的感音神经性聋中，表达会发生相应变化。我们前期研究证实，COX-2抑制剂塞来昔布并不导致动物ABR阈值明显改变，而COX-1抑制剂SC-560却能导致ABR阈值升高。由此我们推测水杨酸耳毒性与COX-1抑制有关。本课题拟采用不同类型COX抑制剂，通过细胞培养和在体动物两种途径，证实水杨酸通过抑制COX-1诱发SGN凋亡，导致永久性聋。本项目的完成将有助于进一步揭示水杨酸耳毒性机制，尽可能规避药物性聋的发生。

Salicylic acid （aspirin）has a good anti-inflammatory effect, but the ototoxicity limits its wide application. Recent clinical studies have found, long-term large dose use of salicylic acid, can lead to permanent hearing loss, basic research has also confirmed that the irreversibility of salicylic acid induced apoptosis of spiral ganglion cells (SGN), but the mechanism is unknown. It has been Known salicylic acid exert their pharmacological effects by inhibiting cyclooxygenase (Cox), and can suppress the two kinds of subtypes Cox-1 and Cox-2, but is still not clear what kind of way is the main cause of ototoxicity. Cox-1, Cox-2 is widely expressed in the cochlea, and in other causes of sensorineural hearing loss, expression of them will change accordingly. We pre verified, Cox-2 Inhibitor Celecoxib does not lead to animal ABR threshold change significantly, while the Cox-1 inhibitor SC-560 can lead to elevated ABR thresholds. Thus we hypothesized that salicylate ototoxicity were due to the suppressed of the Cox-1. The study will use several different types of Cox inhibitors, with cell culture In vitro and experiment animal in vivo, to further confirmed the damage of spiral ganglion cells were caused by inhibition of Cox-1 induced by salicylic acid, which eventually leading to the permanent hearing loss.The accomplishment of this project will help to further reveal the mechanism of salicylate ototoxicity, as far as possible to avoid the occurrence of this drug deafness.