Amifostine and Melatonin Prevent Acute Salivary Gland Dysfunction 10 Days After Radiation Through Anti-Ferroptosis and Anti-Ferritinophagy Effects

Irradiation of the head and neck inevitably leads to decreased salivary gland function. It is postulated that radiation generates excessive reactive oxygen species (ROS) and reduces salivary gland function by ferroptosis, a new cell death mechanism; however, research in this area is currently lacking. In this study, we investigated the effects of amifostine and melatonin on acute salivary gland dysfunction and ferroptosis. Thirty-two Sprague Dawley rats were divided into four groups: control, radiation, radiation + amifostine, and radiation + melatonin. ROS; iron levels; glutathione peroxidase 4; 4-hydroxynonenal; various cytokines; and fibrosis and salivary gland functional markers were measured. Western blotting was used to detect ferritinophagy. After irradiation, we observed an increase in iron levels, ROS generation, oxidized glutathione, lipid peroxidation, fibrosis, and salivary gland dysfunction and a decrease in glutathione peroxidase 4 in salivary gland tissue. Treatment with amifostine or melatonin decreased the ferroptotic response and improved acute salivary gland function 10 days after radiation. The increase in iron levels associated with ferritinophagy was reduced after treatment with amifostine or melatonin. Our results demonstrate that radiation-induced acute salivary gland dysfunction is associated with ferroptosis and ferritinophagy. Amifostine and melatonin inhibit radiation-induced ferroptosis and ferritinophagy in the salivary gland and prevent acute salivary gland dysfunction 10 days after radiation.