Ellagic Acid Reduces Cadmium Exposure-Induced Apoptosis in HT22 Cells via Inhibiting Oxidative Stress and Mitochondrial Dysfunction and Activating Nrf2/HO-1 Pathway

Exposure to cadmium sulfate (CdSO₄) can lead to neurotoxicity. Nevertheless, the precise molecular mechanisms underlying this phenomenon remain unclear, and effective treatment strategies are scarce. This study explored the protective effects of ellagic acid (EA), a natural polyphenolic compound, against CdSO₄ exposure-induced neurotoxicity in HT22 cells and the underlying molecular mechanisms. Our findings demonstrated that exposure of HT22 cells to CdSO₄ resulted in Apoptosis, which was effectively reversed by EA in a dose-dependent manner. EA supplementation also decreased Reactive Oxygen Species (ROS) and mitochondrial ROS production, reduced malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, EA supplementation at 5-20 μM significantly counteracted Cd-induced the loss of mitochondrial membrane potential and the decrease of ATP and reduced the ratio of Bax/Bcl-2 and cleaved-caspase-3 protein expression. Furthermore, EA supplementation resulted in the upregulation of Nrf2 and HO-1 protein and mRNAs while simultaneously downregulating the phosphorylation of JNK and p38 proteins. The pharmacological inhibition of c-Jun N-terminal kinase (JNK) partially attenuated the activation of the Nrf2/HO-1 pathway induced by CdSO₄ and exacerbated its cytotoxic effects. In conclusion, our findings suggest that ethyl acetate (EA) supplementation offers protective effects against CdSO₄-induced Apoptosis in HT22 cells by inhibiting oxidative stress and activating the Nrf2 signaling pathway. Furthermore, the activation of the JNK pathway appears to play a protective role in CdSO₄-induced Apoptosis in HT22 cells.

JNK pathway; Nrf2/HO-1 pathway; apoptosis; cadmium; ellagic acid; oxidative stress.