Salidroside Alleviates Fluoride-Induced Pyroptosis and Developmental Neurotoxicity Through P2X7R/NF-κB/NLRP3 Pathway

Fluoride can cause damage to neurons, but the specific mechanisms remain unclear. Neuronal pyroptosis is associated with cognitive dysfunction, but previous studies mainly focused on hippocampal impairments. This study aimed to whether the P2X7R/NF-κB/NLRP3 pathway would trigger pyroptosis in striatal neurons, thereby mediating neurotoxicity of fluoride, and to evaluate the therapeutic potential of salidroside (Sal). Sal, a key bioactive compound derived from Rhodiola rosea, has been reported that it mainly reduces cell pyroptosis by inhibiting the P2X7R/NF-κB/NLRP3 regulatory axis, thereby improving the neurological function in the brain injury models. Therefore, this study explored, this study investigated its potential protective effects against fluoride-induced neurotoxicity. Therefore, an in vivo model of the second-generation (F2) SD rats and an in vitro model of NG108-15 cells exposed to fluoride with Sal intervention were established. The radial arm maze (RAM) was used to measure neurobehavioral changes. Hematoxylin-Eosin (HE) and transmission electron microscopy (TEM) were used to observe histopathological and ultrastructural changes in the striatum of F2 rats. Cell viability and the expressions of pyroptosis-related proteins were measured using biochemical methods. HE staining demonstrated striatal neuronal degeneration in fluoride-exposed groups, the RAM test indicated neurobehavioral defects, and TEM identified ultrastructural neuronal damage. Fluoride activated the P2X7R/NF-κB/NLRP3 pathway, promoting pyroptosis and impairing the memory ability in F2 rats. Mechanistically, Sal mitigated fluoride-induced neuronal loss by blocking P2X7R/NF-κB/NLRP3 signaling and pyroptotic cell death. In summary, these findings suggest the P2X7R/NF-κB/NLRP3 axis mediates fluoride-induced striatal pyroptosis and neurotoxicity, positioning salidroside as a promising therapeutic candidate.