High‐mobility Group Protein 1/ Receptor for Advanced Glycation End Products/ Nuclear Factor‐κB Signalling Pathway Contributes to the Pathogenic Process of Striatal Neuron Impairment in the Rat Model of Parkinson's Disease

ABSTRACT Background 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. Methods 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. Results (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. Conclusion 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.