University of Tübingen, Department of Otolaryngology, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, Tübingen, Germany.
Nat Med. 2012 Jan 22;18(2):252-9. doi: 10.1038/nm.2634.
Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.
噪声性听力损失(NIHL)是一种具有重大病理生理学和社会后果的全球健康危害,目前尚无有效的治疗方法。在心脏、肺和其他器官中,环鸟苷单磷酸(cGMP)促进了对创伤事件的保护过程。因此,我们分析了编码 cGMP 依赖性蛋白激酶 I(Prkg1)的基因缺失的小鼠的 NIHL,发现与没有缺失的小鼠相比,这些小鼠对 NIHL 的易感性更大,恢复程度明显更低。Prkg1 在野生型小鼠内耳的感觉细胞和神经元中表达,其表达与 cGMP 水解磷酸二酯酶 5(Pde5)的表达谱部分重叠。用 PDE5 抑制剂伐地那非对大鼠和野生型小鼠进行治疗几乎完全预防了 NIHL,并导致毛细胞和螺旋神经节中 Prkg1 依赖性聚(ADP-核糖)的上调,表明存在一种内源性的保护性 cGMP-Prkg1 信号通路,最终导致聚(ADP-核糖)聚合酶的激活。这些数据表明伐地那非或相关药物可能是治疗 NIHL 的候选药物。