Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, PR China; Key Laboratory of Bioengineering Medicine of Guangdong Province, Guangzhou, 510632, Guangdong, PR China; Biomedical Engineering Postdoctoral Research Station, Jinan University, Guangzhou, 510632, Guangdong, PR China.
Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, PR China; Key Laboratory of Bioengineering Medicine of Guangdong Province, Guangzhou, 510632, Guangdong, PR China.
Eur J Pharmacol. 2019 Oct 15;861:172534. doi: 10.1016/j.ejphar.2019.172534. Epub 2019 Jul 13.
Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha that has a variety of biological activities in multiple diseases. Spinal and bulbar muscular atrophy (SBMA) is a late-onset neurodegenerative neuromuscular disease without effective therapy, and the protein toxicity of androgen-dependent polyglutamine-expanded androgen receptor is thought to contribute to its etiology. To determine the therapeutic potential of cepharanthine in SBMA, a murine neuron cell model of SBMA was set up, bearing the human polyglutamine-expanded androgen receptor gene with the Tet-On system. Using this model, we found that the semi-synthetic cepharanthine derivative, cepharanthine hydrochloride (CH), decreased protein levels of polyglutamine-expanded androgen receptor in the cytoplasm and nucleus. Mechanically, CH induced intact autophagy flux and enhanced the clearance of cytoplasmic polyglutamine-expanded androgen receptor, which is different from ubiquitin/proteasome degradation of wild-type androgen receptor. Autophagy induced by CH exhibited cellular protective effects against cytotoxicity of mutant androgen receptor as shown by reduced apoptotic marker and apoptotic cell count. Additionally, activities of cell energy sensor-AMPK signal and intracellular ATP were diminished under CH treatment. In conclusion, this study showed that CH degraded polyglutamine-expanded androgen receptor proteins through an autophagy pathway in neuron cells, resulting in cellular protective effects against toxicity of polyQ expanded proteins. These findings may provide new strategies for the treatment of SBMA and other autophagy-related diseases. Furthermore, the clinical safety and compliance of cepharanthine may make it preferable to current autophagy inducers that may cause undesirable side effects in the treatment of autophagy-related diseases.
石蒜裂碱是一种从石蒜中提取的双稠吡咯啶生物碱，在多种疾病中具有多种生物学活性。脊髓延髓肌萎缩症（SBMA）是一种迟发性神经退行性神经肌肉疾病，目前尚无有效的治疗方法，雄激素依赖性多聚谷氨酰胺扩展型雄激素受体的蛋白毒性被认为与其发病机制有关。为了确定石蒜裂碱在 SBMA 中的治疗潜力，建立了携带 Tet-On 系统的人多聚谷氨酰胺扩展型雄激素受体基因的 SBMA 小鼠神经元细胞模型。使用该模型，我们发现半合成石蒜裂碱衍生物盐酸石蒜裂碱（CH）降低了细胞质和细胞核中多聚谷氨酰胺扩展型雄激素受体的蛋白水平。从机制上讲，CH 诱导完整的自噬流，并增强细胞质中多聚谷氨酰胺扩展型雄激素受体的清除，这与野生型雄激素受体的泛素/蛋白酶体降解不同。CH 诱导的自噬表现出对突变型雄激素受体细胞毒性的细胞保护作用，表现为凋亡标志物减少和凋亡细胞计数减少。此外，CH 处理后细胞能量传感器-AMPK 信号和细胞内 ATP 的活性降低。总之，这项研究表明，CH 通过神经元细胞中的自噬途径降解多聚谷氨酰胺扩展型雄激素受体蛋白，从而对多聚 Q 扩展蛋白的毒性产生细胞保护作用。这些发现可能为 SBMA 和其他自噬相关疾病的治疗提供新的策略。此外，石蒜裂碱的临床安全性和顺应性可能使其优于目前可能在治疗自噬相关疾病时引起不良副作用的自噬诱导剂。
