Oral efficacy of structurally defined chondroitin sulfate Co-administered with SNAC in Parkinson's disease.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited therapeutic options and suboptimal long-term efficacy. Although glycosaminoglycans such as chondroitin sulfate (CS) possess neuroprotective potential, their clinical application is hampered by poor oral bioavailability and limited target specificity. In this study, we first established a highly sensitive LC-MS/MS MRM assay to quantify CS in plasma. Using animal models, we demonstrated that co-administration with N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) significantly enhanced the oral bioavailability of CS compared to deoxycholic acid (DOCA) modification. Subsequently, we synthesized a structurally defined 6-O-desulfated chondroitin sulfate octasaccharide (CS-dp8-de6S) and evaluated its therapeutic efficacy in MPTP-induced PD mouse models via co-administration with SNAC. Treatment with CS-dp8-de6S/SNAC improved motor performance in the pole and hanging tests, partially restored striatal dopamine levels, and upregulated tyrosine hydroxylase expression in the substantia nigra, these effects were significantly greater than those observed with non-desulfated CS-dp8, demonstrating its enhanced specificity. Mechanistic studies using gel mobility shift assay and dual immunohistochemistry revealed that CS-dp8-de6S treatment effectively reduced pathological fibrinogen β-chain (FGB) deposition in brain tissues. These findings highlight the potential of structurally defined CS oligosaccharides as novel disease-modifying therapeutics for PD and provide a basis for the development of carbohydrate-based strategies targeting proteinopathies in neurodegenerative disorders.