High-mobility Group Protein 1/ Receptor for Advanced Glycation End Products/ Nuclear Factor-κB Signalling Pathway...

High-mobility group protein 1 (HMGB1) is a ligand known to bind to the receptor for advanced glycation end products (RAGE), and it can activate nuclear factor-κB (NF-κB) to mediate cellular damage. RAGE and Parkinson's disease (PD) are closely associated, but it remains unclear whether the HMGB1/RAGE/NF-κB signaling pathway contributes to the pathophysiology of PD.

PD was induced by administration of 6-hydroxydopamine (6-OHDA), while RAGE was inhibited using an inhibitor, FPS-ZM1. The grip strength test and Morris water maze were used to evaluate sensorimotor and memory skills. Then detect the expression levels of RAGE, HMGB1, and NF-κB in the striatal sample using immunohistochemistry, western blotting, and RT-qPCR.

(1) In PD rats, treatment with FPS-ZM1 improved learning and memory ability and alleviated sensorimotor deficits. (2) The striatum of PD rats exhibited a significant increase in the number of HMGB1-, RAGE-, and NF-κB-positive cells, which could be reduced through the administration of FPS-ZM1. Immunofluorescence double-labeling results indicated that NeuN-positive neurons were the primary sites of HMGB1-, RAGE-, and NF-κB-positive responses. Furthermore, these double-labeled neurons demonstrated a significant increase following 6-OHDA-induced depletion of striatal dopamine (DA). However, the FPS-ZM1 administration considerably attenuated these changes. (3) The treatment of FPS-ZM1 significantly reduced the increase in protein expression of HMGB1, RAGE, and NF-κB that followed striatal DA depletion. Similarly, NF-κB and RAGE mRNA expression were increased by striatal DA deprivation; however, injection of FPS-ZM1 significantly reduced these changes.

The HMGB1/RAGE/NF-κB signaling pathway plays a critical role in the pathogenesis of striatal neuronal damage in PD, highlighting its potential as a therapeutic target.