Curcumin-Derived J147 Protects HT22 Cells from Cell Death Under Tunicamycin-Induced Endoplasmic Reticulum Stress with CHOP Suppression Retained After ATP5A Knockdown

Oxidative stress and proteotoxic endoplasmic reticulum (ER) stress are interconnected cellular stress processes implicated in neuronal injury. J147 reportedly exerts neuroprotective effects through ATP synthase α-subunit (ATP5A)-associated mitochondrial mechanisms, but whether it protects cells from death under proteotoxic ER stress through the same mechanism remains unclear. Here, we directly compared curcumin, CNB-001, and J147 under glutamate-induced oxytosis and tunicamycin (TM)-induced ER stress in murine hippocampal HT22 cells. MTT reduction assays showed that all three compounds attenuated glutamate-induced cell death, whereas only J147 protected cells from TM-induced cytotoxicity at a submicromolar range. LIVE/DEAD staining confirmed the protective effects of J147 against both stressors. At the molecular level, J147 suppressed the TM-induced upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) at the mRNA and protein levels without suppressing the adaptive ER chaperone glucose-regulated protein 78. ATP5A knockdown attenuated glutamate-induced oxytosis but did not protect against TM-induced cell death, and J147 retained its protective effect after ATP5A knockdown. These findings support stressor-dependent protective actions of J147 involving an ATP5A-associated mechanism against oxidative stress and an ATP5A-independent mechanism associated with suppression of CHOP induction. J147 may therefore provide a useful pharmacological tool for investigating neuronal responses to interconnected oxidative and proteotoxic stress.