Caspase inhibitor facilitates recovery of hearing by protecting the cochlear lateral wall from acute cochlear mitochondrial dysfunction
Caspase inhibitor facilitates recovery of hearing by protecting the cochlear lateral wall from acute cochlear mitochondrial dysfunction
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DOI：
10.1002/jnr.21470
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发表时间：
2008-01-01
影响因子：
4.2
通讯作者：
Ogawa, Kaoru
中科院分区：
文献类型：
--
作者：
Mizutari, Kunio;Matsunaga, Tatsuo;Ogawa, Kaoru
我们最近发现，局部给药线粒体毒素3-硝基丙酸（3-NP）引起的大鼠耳蜗急性能量衰竭主要是由于耳蜗侧壁纤维细胞变性引起的听力损失。在本研究中，我们分析了泛caspase抑制剂z-Val-AlaAsp(Ome)-氟甲基酮（Z-VAD-FMK）对3- np诱导的听力损失的影响，该模型在低频时出现暂时阈值移位，在高频时出现永久性阈值移位。模型大鼠在3- np治疗前1天开始腹腔注射Z-VAD-FMK或对照物3天。给药1天后，20 kHz时Z-VAD-FMK组听觉脑干反应（ABR）阈值升高至70 dB，对照组升高至85 dB。Z-VAD-FMK组在14天内完全恢复到术前水平，而在对照组中，即使在给药3-NP后28天，ABR阈值仍保持在50 dB的水平。Z-VAD-FMK治疗也改善了8 kHz时的听力恢复，但对40 kHz时的听力恢复没有影响。组织学检查表明，Z-VAD-FMK治疗可抑制耳蜗基底转侧壁纤维细胞的进行性变性，以及这些纤维细胞的凋亡。这些结果清楚地表明，在本动物模型中，耳蜗外壁caspase依赖性纤维细胞凋亡在听力损失中起重要作用。此外，本研究的结果表明，对于耳蜗缺血等急性能量衰竭引起的感音神经性听力损失，系统给予半胱天蛋白酶抑制剂可能是一种有效的治疗方法。(c) 2007 Wiley-Liss, Inc。
We recently showed that acute energy failure in the rat cochlea induced by local administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) causes hearing loss mainly due to degeneration of cochlear lateral-wall fibrocytes. In the present study, we analyzed the effect of the pan-caspase inhibitor z-Val-AlaAsp(Ome)-f luoromethyl ketone (Z-VAD-FMK) on 3-NP-induced hearing loss in a model showing temporary threshold shifts at low frequencies and permanent threshold shifts at high frequencies. The model rats received an intraperitoneal injection of either Z-VAD-FMK or vehicle for 3 days starting 1 day prior to 3-NP treatment. One day after the administration of 3-NP, the auditory brain-stem response (ABR) threshold at 20 kHz was elevated to 70 dB in the Z-VAD-FMK group and to 85 dB in controls. The Z-VAD-FMK group completely recovered to the preoperative level within 14 days, whereas in the controls, the ABR threshold remained elevated at 50 dB even 28 days after the administration of 3-NP. Treatment with Z-VAD-FMK also improved recovery of hearing at 8 kHz but did not change recovery at 40 kHz. Histological examination demonstrated that treatment with Z-VAD-FMK inhibited progressive degeneration of the lateral-wall fibrocytes in the cochlear basal turn, as well as apoptosis of these fibrocytes. These results clearly indicate that caspase-dependent apoptosis of fibrocytes in the cochlear lateral wall plays an important role in hearing loss in the present animal model. Moreover, the results of the present study suggest that systemic administration of a caspase inhibitor may be an effective therapy for sensorineural hearing loss caused by acute energy failure such as that observed in cochlear ischemia. (c) 2007 Wiley-Liss, Inc.