Du Hongjie, Zhou Xuanchen, Shi Lei, Xia Ming, Wang Yajie, Guo Na, Hu Houyang, Zhang Pan, Yang Huiming, Zhu Fangyuan, Teng Zhenxiao, Liu Chengcheng, Zhao Miaoqing
Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Qilu Pharmaceutical Co., Ltd., Jinan, China.
Front Mol Neurosci. 2022 Feb 24;15:829642. doi: 10.3389/fnmol.2022.829642. eCollection 2022.
The molecular mechanisms that regulate the proliferation and differentiation of inner ear spiral ganglion cells (SGCs) remain largely unknown. Shikonin (a naphthoquinone pigment isolated from the traditional Chinese herbal medicine comfrey root) has anti-oxidation, anti-apoptosis and promoting proliferation and differentiation effects on neural progenitor cells. To study the protective effect of shikonin on auditory nerve damage, we isolated spiral ganglion neuron cells (SGNs) and spiral ganglion Schwann cells (SGSs) that provide nutrients and pretreated them with shikonin. We found that shikonin can reduce ouabain, a drug that can selectively destroy SGNs and induce auditory nerve damage, caused SGNs proliferation decreased, neurite outgrowth inhibition, cells apoptosis and mitochondrial depolarization. In addition, we found that shikonin can increase the expression of Nrf2 and its downstream molecules HO-1 and NQO1, thereby enhancing the antioxidant capacity of SGNs and SGSs, promoting cells proliferation, and inhibiting cells apoptosis by activating the Nrf2/antioxidant response elements (ARE) signal pathway. However, knockdown of Nrf2 rescued the protective effect of shikonin on SGNs and SGSs damage. In addition, we injected shikonin pretreatment into mouse that ouabain-induced hearing loss and found that shikonin pretreatment has a defensive effect on auditory nerve damage. In summary, the results of this study indicate that shikonin could attenuate the level of oxidative stress in SGNs and SGSs through the Nrf2-ARE signaling pathway activated, induce the proliferation and differentiation of SGNs, and thereby improve the neurological hearing damage in mice. Therefore, shikonin may be a candidate therapeutic drug for endogenous antioxidants that can be used to treat neurological deafness.
调节内耳螺旋神经节细胞（SGCs）增殖和分化的分子机制在很大程度上仍不清楚。紫草素（一种从传统中药紫草根部分离出的萘醌色素）对神经祖细胞具有抗氧化、抗凋亡以及促进增殖和分化的作用。为了研究紫草素对听神经损伤的保护作用，我们分离了提供营养的螺旋神经节神经元细胞（SGNs）和螺旋神经节雪旺细胞（SGSs），并用紫草素对它们进行预处理。我们发现紫草素可以减轻哇巴因（一种能选择性破坏SGNs并诱导听神经损伤的药物）导致的SGNs增殖减少、神经突生长抑制、细胞凋亡和线粒体去极化。此外，我们发现紫草素可以增加Nrf2及其下游分子HO-1和NQO1的表达，从而增强SGNs和SGSs的抗氧化能力，促进细胞增殖，并通过激活Nrf2/抗氧化反应元件（ARE）信号通路抑制细胞凋亡。然而，敲低Nrf2可挽救紫草素对SGNs和SGSs损伤的保护作用。此外，我们将紫草素预处理注射到哇巴因诱导听力损失的小鼠体内，发现紫草素预处理对听神经损伤具有防御作用。总之，本研究结果表明，紫草素可通过激活Nrf2-ARE信号通路减轻SGNs和SGSs中的氧化应激水平，诱导SGNs的增殖和分化，从而改善小鼠的神经性听力损伤。因此，紫草素可能是一种内源性抗氧化剂候选治疗药物，可用于治疗神经性耳聋。
