18β-Glycyrrhetinic acid attenuates endoplasmic reticulum stress and neuroinflammation via the PI3K/AKT-dependent pathway in MPTP/p-induced Parkinson's disease mouse model.

Neuronal death in Parkinson's disease (PD) is driven by mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and α-synuclein aggregation. This study investigates the neuroprotective potential of 18β-Glycyrrhetinic acid (18βGA) in a chronic MPTP/probenecid (MPTP/p)-induced mouse model of PD. Behavioural assessments demonstrates that 18βGA significantly ameliorated MPTP/p-induced motor impairments. Biochemical analyses revealed that 18βGA markedly restored the activities of electron transport chain complexes I-V, reduced intracellular reactive oxygen species (ROS) accumulation, and preserved mitochondrial membrane potential disrupted by MPTP/p exposure. Enzyme-linked immunosorbent assay (ELISA) further showed that 18βGA reduced pro-inflammatory cytokine levels (TNF-α and IL-1β), restored antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase), and decreased malondialdehyde (MDA) levels. Immunoblotting and Immunofluorescence analysis revealed preservation of tyrosine hydroxylase-positive dopaminergic neurons, accompanied by reduced α-synuclein accumulation and decreased BiP (GRP78) expression in the substantia nigra. Western blot analyses confirmed downregulation of ER stress markers (BiP and CHOP), inflammatory mediators (TNF-α and NF-κB), and pro-apoptotic proteins (Bax and cleaved caspase-3), along with upregulation of the anti-apoptotic protein BCL2 and activation of the PI3K/AKT signalling pathway following 18βGA treatment. Collectively, these findings demonstrate that 18βGA exerts robust neuroprotective effects by attenuating mitochondrial dysfunction, oxidative stress, ER stress, inflammation, and apoptosis, highlighting its potential as a promising therapeutic candidate for Parkinson's disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04757-4.