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

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.