Salidroside alleviates cadmium-induced toxicity in mice by restoring the notch/HES-1 and RIP1-driven inflammatory signaling axis

Salidroside (SAL) is a marker glycoside of Rhodiola rosea with significant antioxidant, anti-inflammatory, and other health benefits. In this study, we determined its neuroprotective effects against Cd-induced toxicity in cultured cells and mice.GL261 cell and Cd-intoxicated mouse model were used. ICP-MS and MWM were performed to measure Cd content and Cd-induced cognitive impairment in mice, respectively.SAL attenuated Cd toxicity in GL261 cells as well as protected mice from substantial organic damage and cognitive deficits. SAL treatment alleviated Cd-induced oxidative stress, glial cell activation, and elevation of pro-inflammatory factors including TNF-α, IL-1β, and IL-6. Cd-induced cognitive deficits observed in the Morris water maze in mice were rescued by SAL. At the mechanistic level, SAL maintained the activity of antioxidant enzymes such as SOD and GSH-Px in the serum and brain, and scavenged the peroxidation product MDA, thereby restoring redox homeostasis in vivo, attenuating neuronal damage, and ultimately antagonized Cd-induced toxicity. Furthermore, Cd activated the RIP1-driven inflammatory signaling pathway and Notch/HES-1 signaling axis in the brain, leading to inflammation and neuronal loss, which could be attenuated by SAL.SAL is a natural product with good anti-Cd effects, indicating that Rhodiola rosea is promising plant that is worthy of cultivation for health and economic benefits.