Cordycepin exacerbates cadmium-induced neurotoxicity via promoting endoplasmic reticulum stress-associated apoptosis

• Exposure of Cor deteriorated Cd-induced learning and memory deficits in mice. • Cor promoted Cd-induced neuronal apoptosis both in vivo and vitro. • The ER stress pathway was involved in the increased Cd- and Cor-induced neurotoxicity. Cordycepin (Cor) is a potent bioactive constituent of Cordyceps militaris , which has been used as a daily tonic food and herbal medicine in Asia. Cadmium (Cd) is a widespread neurotoxic environmental contaminant, and it has been detected as a pollutant in Cordyceps militaris . However, the potential effects of Cor on Cd neurotoxicity remains unknown. This study aimed to investigate the effects and possible mechanisms of Cor on neurotoxicity in Cd-induced cell and preclinical models. It was observed that Cor administration aggravated Cd-induced cognitive impairment and neurotoxicity in mice, exerted synergistic growth inhibition, and promoted apoptosis of SH-SY5Y cells. These effects were found to be mediated through the activation of endoplasmic reticulum (ER) stress. Overall, our findings suggest that Cor can increase Cd-induced neurotoxicity via promoting ER stress-associated apoptosis. These observations may support the implementation of stricter criterion for the detection of Cd in Cordyceps militaris , to keep the consumers safe.