Department of Biomedical Sciences and Centre of Reproduction, Development and Aging (CRDA), University of Macau, Taipa, Macau.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau.
Free Radic Biol Med. 2023 Nov 1;208:299-308. doi: 10.1016/j.freeradbiomed.2023.08.021. Epub 2023 Aug 23.
Progressive death of dopaminergic (DA) neurons is the main cause of Parkinson's disease (PD). The discovery of drug candidates to prevent DA neuronal death is required to address the pathological aspects and alter the process of PD. Azoramide is a new small molecule compound targeting ER stress, which was originally developed for the treatment of diabetes. In this study, pre-treatment with Azoramide was found to suppress mitochondria-targeting neurotoxin MPP-induced DA neuronal death and locomotor defects in zebrafish larvae. Further study showed that pre-treatment with Azoramide significantly attenuated MPP-induced SH-SY5Y cell death by reducing aberrant changes in nuclear morphology, mitochondrial membrane potential, intracellular reactive oxygen species, and apoptotic biomarkers. The mechanistic study revealed that Azoramide was able to up-regulate the expression of ER chaperone BiP and thereby prevented MPP-induced BiP decrease. Furthermore, pre-treatment with Azoramide failed to suppress MPP-induced cytotoxicity in the presence of the BiP inhibitor HA15. Taken together, these results suggested that Azoramide is a potential neuroprotectant with pro-survival effects against MPP-induced cell death through up-regulating BiP expression.
多巴胺能（DA）神经元的进行性死亡是帕金森病（PD）的主要原因。需要发现预防 DA 神经元死亡的药物候选物来解决病理方面的问题并改变 PD 的进程。阿佐酰胺是一种针对内质网应激的新型小分子化合物，最初是为治疗糖尿病而开发的。本研究发现，阿佐酰胺预处理可抑制线粒体靶向神经毒素 MPP 诱导的斑马鱼幼虫 DA 神经元死亡和运动缺陷。进一步的研究表明，阿佐酰胺预处理通过减少核形态、线粒体膜电位、细胞内活性氧和凋亡生物标志物的异常变化，显著减轻 MPP 诱导的 SH-SY5Y 细胞死亡。机制研究表明，阿佐酰胺能够上调内质网伴侣 BiP 的表达，从而防止 MPP 诱导的 BiP 减少。此外，在 BiP 抑制剂 HA15 的存在下，阿佐酰胺预处理不能抑制 MPP 诱导的细胞毒性。总之，这些结果表明，阿佐酰胺是一种潜在的神经保护剂，通过上调 BiP 表达对 MPP 诱导的细胞死亡具有生存促进作用。
