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

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

  • Sci Rep. 2025 Aug 13;15(1):29760. doi: 10.1038/s41598-025-14631-7.
Fujun Ai # 1 2,  Shengyuan Wang # 3,  Ling Ye 4,  Wen Wan 5,  Xiao Zhou 1 2,  Minghai Liu 4,  Kaiju Mo 1 2,  Yongheng Lu 1 2,  Na Wei 1 2,  Zhizhong Guan 1 2 5,  Yanjie Liu 6 7 8
Affiliations

Affiliations

  • 1 Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
  • 2 Pathology Morphology and Molecular Laboratory of the Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
  • 3 Department of Pathology, Lin Yi People's Hospital, Linyi, Shandong, China.
  • 4 Department of Neurology, The People's Hospital of Huaxi District, Guiyang, 550025, China.
  • 5 Department of Pathology, Guizhou Medical University, Guiyang, 550004, Guizhou, China.
  • 6 Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China. liuyanjie@gmc.edu.cn.
  • 7 Pathology Morphology and Molecular Laboratory of the Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China. liuyanjie@gmc.edu.cn.
  • 8 Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education, Guizhou Medical University, Guiyang, 550004, China. liuyanjie@gmc.edu.cn.
  • # Contributed equally.
PMID: 40804089 DOI: 10.1038/s41598-025-14631-7
Abstract

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.

Keywords

Chondroitin sulfate; Erk1/2; Fluoride; MMP-2; MMP-9; SYN.

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