Crosstalk between α-synuclein accumulation, NLRP3 inflammasome activation, oxidative stress, and apoptosis in a rotenone-induced Parkinson rat model.
TL;DR
A synergistic pathogenic cascade where α-synuclein accumulation contributes to neuroinflammation and oxidative stress, suppressing antioxidant defenses and activating apoptotic pathways is suggested, ultimately leading to dopaminergic neuron death and severe motor dysfunction.
Abstract
Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. This study aimed to elucidate the dynamic interplay between these pathological pathways in a rotenone-induced rat model of PD. Adult male Wistar rats were chronically treated with rotenone. Behavioral assessments included Rotarod, Open Field, Rotating Pole, and Cylinder tests. On days 7, 14, and 21, gene expression levels of key markers including α-synuclein, NLRP3 inflammasome components (NLRP3, ASC), inflammatory cytokines (IL-1β, TNF-α, IL-6), upstream signaling molecules (TLR4, NF-κB), antioxidant defense factors (Nrf2, HO-1), apoptotic regulators (Bax, Bcl-2, Caspase-3), and tyrosine hydroxylase (TH) were quantified via qPCR. Crucially, protein abundance for all major markers was validated using ELISA, alongside biochemical assessment of oxidative stress markers (MDA and SOD). Rotenone treatment caused a progressive decline in motor performance across all behavioral assays (p < 0.001), including reduced rotarod latency, decreased open field distance, increased pole test latency, and heightened cylinder asymmetry. The PD group exhibited significant time-dependent increases in α-synuclein, TLR4, NF-κB, NLRP3, ASC, IL-1β, IL-6, TNF-α, Bax, Caspase-3, and MDA levels. Conversely, expression levels of Nrf2, HO-1, Bcl-2, and SOD activity showed marked decreases (p < 0.01). Finally, TH expression decreased progressively, reaching roughly 50% of control levels at day 21. Correlation analysis confirmed strong links between α-synuclein accumulation, inflammation, oxidative damage, and neuronal loss. These findings suggest a synergistic pathogenic cascade where α-synuclein accumulation contributes to neuroinflammation and oxidative stress, suppressing antioxidant defenses and activating apoptotic pathways, ultimately leading to dopaminergic neuron death and severe motor dysfunction.