Cadmium Chloride Induces Memory Deficits and Hippocampal Damage by Activating the JNK/p⁶⁶Shc/NADPH Oxidase Axis

This study investigated whether the mechanism underlying the neurotoxic effects of cadmium chloride (CdCl₂) in rats involves p⁶⁶Shc. This study comprised an initial in vivo experiment followed by an in vitro experiment. For the in vivo experiment, male rats were orally administered saline (vehicle) or CdCl₂ (0.05 mg/kg) for 30 days. Thereafter, spatial and retention memory of rats were tested and their hippocampi were used for biochemical and molecular analyses. For the in vitro experiment, control or p⁶⁶Shc-deficient hippocampal cells were treated with CdCl₂ (25 µM) in the presence or absence of SP600125, a c-Jun N-terminal kinase (JNK) inhibitor. Cadmium chloride impaired the spatial learning and retention memory of rats; depleted levels of glutathione and manganese superoxide dismutase; increased reactive oxygen species (ROS), tumor necrosis factor α, and interleukin 6; and induced nuclear factor kappa B activation. Cadmium chloride also decreased the number of pyramidal cells in the CA1 region and induced severe damage to the mitochondria and endoplasmic reticulum of cells in the hippocampi of rats. Moreover, CdCl₂ increased the total unphosphorylated p66Shc, phosphorylated (Ser³⁶) p⁶⁶Shc, phosphorylated JNK, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, cytochrome c, and cleaved caspase-3. A dose-response increase in cell death, ROS, DNA damage, p⁶⁶Shc, and NADPH oxidase was also observed in cultured hippocampal cells treated with CdCl₂. Of note, all of these biochemical changes were attenuated by silencing p⁶⁶Shc or inhibiting JNK with SP600125. In conclusion, CdCl₂ induces hippocampal ROS generation and apoptosis by promoting the JNK-mediated activation of p⁶⁶Shc.