Azoramide prevents MPP⁺-induced dopaminergic neuronal death via upregulating ER chaperone BiP expression

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.