Development of treatment modalities for ischemic cochlear damage

基于细胞凋亡机制探讨内耳缺血对耳蜗损伤的预防作用。我们选用蒙古国沙鼠作为实验动物，蒙古国沙鼠缺乏大脑后交通动脉，其迷路动脉完全由椎动脉滋养。通过阻断双椎动脉15分钟，对动物进行缺血性损伤。缺血引起CAP阈值升高20 dB。组织学上毛细胞和螺旋神经节细胞发生散发性变性，而血管纹的损伤是可逆的。证实变性是由细胞凋亡引起的，在缺血12小时时最明显，3天后不再可见。评估了各种治疗方式是否以及如何预防耳蜗缺血再灌注损伤。1.伊达拉邦（MCI-186）是一种自由基清除剂，在缺血1小时后静脉给药，可有效防止CAP阈值升高和毛细胞降解。2.将体温降低至32度（低温）完全阻断内耳的降解，主要是通过阻止淋巴周围谷氨酸的释放，减少超氧化物的产生，降低内耳的代谢率。3.人参皂苷Rb1属Kanpo药，对缺血性耳蜗损伤也有预防作用。4.AMPA/kainate型谷氨酸拮抗剂如DNQX对耳蜗损伤的预防效果显著，而NMDA型如D-AP5对耳蜗损伤的预防作用有限。5. GDNF与变性腺病毒结合后，直接注入内耳，可显著降低因缺血引起的耳蜗损伤。

Prevention of cochlear damage due to inner ear ischemia was investigated based on the underlying apoptotic mechanism. We used Mongolian gerbils as experimental animals, which lack the posterior cerebral communicating arteries and have labyrinthine arteries nourished solely by the vertebral arteries. The animals were subjected to ischemic insult by occluding both vertebral arteries for 15 min. The ischemia caused 20 dB of increase in CAP threshold. Histologically the hair cells and spiral ganglion cells underwent sporadic degeneration, while the damage to the stria vascularis was reversible. The degeneration was proved to be due to apoptosis, which was most prominent at 12 hours of ischemia and was no longer seen later than 3 days.A variety of treatment modalities were assessed if and how they can prevent ischemia-reperfusion injury of the cochlea. 1.Edarabon (MCI-186) which belongs to a free radical scavenger was proved effective in preventing increase in CAP threshold and degradation of the hair cells, when it was administration intravenously 1 hour after ischemic insult. 2.Lowering of the body temperature to 32 degree (hypothermia) completely blocked degradation of the inner ear, mainly by preventing release of glutamate in the perilymph, reducing production of superoxide and decreasing metabolic rate in the inner ear. 3.Ginsenoside Rb1, which belongs to Kanpo medicine, was also proved effective in prevention of ischemic cochlear damage. 4.AMPA/kainate type of glutamate antagonist such as DNQX was efficient in prevention of cochlear damage, while NMDA type such as D-AP5 had limited value. 5. GDNF which was incorporated in a denatured adenovirus dramatically decreased the cochlear damage due to ischemia, when administered directly into the inner ear.