Development of treatment modalities for ischemic cochlear damage

从细胞凋亡的基本机制出发，探讨了预防内耳缺血所致耳蜗病的作用机制。实验动物为蒙古沙土鼠，缺少大脑后交通动脉，迷路动脉仅由椎动脉提供营养。结扎双侧椎动脉15min，造成动物缺血性损伤。缺血使CAP阈值升高20dB.组织学上，毛细胞和螺旋神经节细胞发生零星变性，而对血管纹的损伤是可逆的。这种变性是由细胞凋亡引起的，在缺血12小时时最明显，超过3天后不再出现。评估了各种治疗方式是否以及如何预防耳蜗骨缺血再灌注损伤。1.Edarabon(MCI-186)是一种自由基清除剂，在脑缺血后1小时静脉给药，能有效地防止CAP阈值升高和毛细胞退化。2.将体温降低到32度(低温)完全阻止内耳的降解，主要是通过阻止外淋巴液中谷氨酸的释放，减少超氧化物的产生，降低内耳的代谢率。3.人参皂苷Rb1为康宝药材，对缺血性耳蜗病也有保护作用。4.AMPA/海人酸型谷氨酸拮抗剂DNQX对耳蜗炎的预防作用较好，而D-AP5等NMDA型耳蜗炎的预防作用有限。5.将GDNF掺入变性的腺病毒中，直接注入内耳，可显著减轻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.