Cadmium Chloride Induces Memory Deficits and Hippocampal Damage by Activating the JNK/p <sup>66</sup> Shc/NADPH Oxidase Axis
Attalla F. El‐kott, Ali S. Alshehri, Heba S. Khalifa, Abd-El-karim Mohamed Abd-Lateif, Mohammad Alshehri, Mona M. Abd El‐Maksoud, Refaat A. Eid, Mashael Mohammed Bin-Meferij
Abstract
This study investigated whether the mechanism underlying the neurotoxic effects of cadmium chloride (CdCl 2 ) in rats involves p 66 Shc. 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 CdCl 2 (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 p 66 Shc-deficient hippocampal cells were treated with CdCl 2 (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, CdCl 2 increased the total unphosphorylated p66Shc, phosphorylated (Ser 36 ) p 66 Shc, phosphorylated JNK, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, cytochrome c, and cleaved caspase-3. A dose–response increase in cell death, ROS, DNA damage, p 66 Shc, and NADPH oxidase was also observed in cultured hippocampal cells treated with CdCl 2 . Of note, all of these biochemical changes were attenuated by silencing p 66 Shc or inhibiting JNK with SP600125. In conclusion, CdCl 2 induces hippocampal ROS generation and apoptosis by promoting the JNK-mediated activation of p 66 Shc.