18β-Glycyrrhetinic Acid Regulates Endoplasmic Reticulum Stress and Autophagy Dysregulation in the MPTP/p-Induced...

Parkinson disease (PD) is marked by a significant reduction in dopaminergic neurons in the substantia nigra pars compacta region of the brain. This neuronal loss is accompanied by aggregation of the α-synuclein protein, persistent endoplasmic reticulum (ER) stress, and disruption in the autophagy process. 18β-Glycyrrhetinic acid (18βGA), an oleanolic acid-type triterpenoid, has been shown to exhibit anti-inflammatory properties and neuroprotective effects. This study is the first to explore the potential neuroprotective effects of 18βGA in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of PD, focusing on the role of ER stress and autophagy and examining the potential underlying mechanisms. MPTP/p-treated mice exhibited impaired motor function and elevated levels of α-synuclein and ER stress markers such as BiP, protein kinase RNA-like ER kinase (p-PERK), phosphorylated inositol-requiring enzyme 1 (p-IRE1), phosphorylated eukaryotic initiation factor α (p-eIF2α), and C/EBP homologous binding protein (CHOP). It also shows autophagy dysregulation, marked by increased phosphorylated c-Jun N-terminal kinase 1 (p-JNK-1), Beclin-1, and microtubule-associated protein 1 light chain 3 (LC3)-II, as well as autophagic vacuoles, and decreased B-cell lymphoma 2 (BCL-2) and p62. Treatment with 18βGA significantly improved motor performance, reduced α-synuclein accumulation, and restored tyrosine hydroxylase (TH) expression. It also attenuated ER stress markers, including BiP, p-PERK, p-IRE1, p-eIF2α, and CHOP. Moreover, 18βGA normalized autophagy-related alterations by decreasing p-JNK-1, Beclin-1, LC3-II, and autophagic vacuole formation, while increasing BCL-2 and p62 expression. These findings suggest that 18βGA confers neuroprotection by suppressing ER stress (via PERK and IRE1α pathways) and modulating autophagy through the BCL-2/Beclin-1 axis. Thus, 18βGA holds promise as a therapeutic candidate for Parkinson disease.