Modulation of PM20D1 expression by rosiglitazone confers neuroprotection in tramadol-induced Parkinsonian rats

Parkinson's disease (PD) is a progressive neurodegenerative disorder with no available disease‑modifying therapy, and tramadol misuse has been increasingly associated with PD‑like neurotoxicity through oxidative stress, mitochondrial dysfunction, and apoptosis. This study investigated whether rosiglitazone (RSG), a PPARγ agonist, confers neuroprotection in tramadol-induced Parkinsonian rats by modulating PM20D1 gene expression, and whether its effects are enhanced in combination with levodopa-carbidopa. Fifty‑six male rats were randomized into seven groups: control, tramadol‑only, RSG (5/10/15 mg/kg) plus tramadol, levodopa-carbidopa plus tramadol, and RSG 5 mg/kg plus levodopa-carbidopa plus tramadol. Tramadol significantly impaired motor function and reduced dopamine compared to controls (serum: 189.0 ± 12.8 vs. 470.0 ± 21.2 pg/mL; brain: 54.8 ± 9.0 vs. 251.0 ± 43.6 pg/mL, p < 0.001), depleted antioxidants (SOD: 58.1 ± 8.5 vs. 155.0 ± 16.3 ng/mL; GSH: 6.9 ± 0.8 vs. 21.6 ± 2.6 µg/mL), and increased apoptosis (caspase‑3: 36.9 ± 3.6 vs. 10.0 ± 2.5 ng/mL). Relative to the tramadol‑only group, RSG dose‑dependently restored dopamine (up to 397.0 ± 23.1 pg/mL), normalized oxidative stress (MDA reduced to 1.5 ± 0.2 ng/mL), and upregulated PM20D1 gene expression (3.2 ± 0.5 fold) and BCL2 gene expression (3.2 ± 0.5 fold). The low-dose RSG plus levodopa-carbidopa combination achieved maximal behavioral recovery and dopamine restoration (1023.0 ± 248.0 pg/mL) compared to the tramadol-only group. These findings provide the first evidence that RSG confers neuroprotection against tramadol-induced Parkinsonism through PPARγ-mediated modulation of PM20D1 gene expression, highlighting a novel translational therapeutic axis with potential disease-modifying implications for PD.