Chondroitin sulfate protects against synaptic impairment caused by fluorosis through the Erk1/2-MMP-9 signaling pathway

Prolonged exposure to fluoride may induce neurotoxic effects. Chondroitin sulfate (CS) exhibits protective functions within the central nervous system (CNS); however, the mechanism by which CS protects synapses against fluoride remains incompletely understood. Our objective was to investigate the protective efficacy of CS on synapses and decipher its underlying mechanisms. We showed that fluoride exposure reduced the expression of synaptic protein synaptophysin (SYN) and impaired learning and memory functions, whereas CS counteracted these alterations, suggesting its protective effect against fluoride-induced cognitive deficits. Further studies revealed disruption of the Erk1/2/MMP-2/MMP-9 signaling pathway both in vivo and in vitro, manifested by increased total Erk1/2, Erk1/2 phosphorylation and MMP-9 expression, along with decreased MMP-2 levels. Importantly, treatment of SH-SY5Y cells with PD98059 or CS attenuated fluoride-induced effects, indicating a regulatory role of CS in the Erk1/2/MMP-9 signaling pathway. However, MMP-2 was not implicated in this process. These data demonstrate the neuroprotective effects of CS and highlight its potential for protecting against fluoride-induced neurotoxicity and synaptic impairment.