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Development of treatment modalities for ischemic cochlear damage

缺血性耳蜗损伤治疗方法的开发

基本信息

批准号：
14370545
负责人：
GYO Kiyofumi
金额：
$ 9.02万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

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.

基于潜在的细胞凋亡机制，研究了由于内耳缺血引起的耳蜗损伤的预防。本研究以蒙古沙土鼠为实验动物，其大脑后交通动脉缺失，而脑动脉仅由椎动脉提供营养。动物进行缺血性损伤闭塞两个椎动脉15分钟。缺血引起CAP阈值增加20分贝。组织学上毛细胞和螺旋神经节细胞发生散在变性，而血管纹的损害是可逆的。结果表明，缺血12 h后耳蜗细胞凋亡最为明显，3 d后细胞凋亡消失。1.依达拉奉（MCI-186）是一种自由基清除剂，在缺血损伤后1小时静脉给药时，可有效防止CAP阈值的升高和毛细胞的降解。2.将体温降至32度（低温）完全阻断了内耳的降解，主要是通过防止外淋巴中谷氨酸的释放，减少超氧化物的产生和降低内耳的代谢率。3.坎波药人参皂苷Rb 1对缺血性耳蜗损伤也有一定的预防作用。4.AMPA/红藻氨酸型谷氨酸拮抗剂如DNQX对耳蜗损伤的保护作用较好，而NMDA型谷氨酸拮抗剂如D-AP 5的保护作用有限。5.将GDNF掺入到变性腺病毒中，当直接施用到内耳中时，可显著降低由于缺血引起的耳蜗损伤。