Abstract
Oxidative stress and changes in lncRNA expression are key factors in the pathophysiology of Parkinson's disease. This study investigated the protective effects of N-acetylcysteine and S-methylcysteine on the expression of long non-coding RNAs and oxidative stress-related genes in the brain, as well as the activity of antioxidant enzymes in the brain and serum of mice with rotenone-induced Parkinson's disease. In this experimental study, 56 male BALB/c mice were utilized and treated continuously for 10 days. Gene expression of superoxide dismutase, glutathione peroxidase, catalase, Nrf2, Ho-1, and long non-coding RNAs Malat1, Neat1, and Gas5 in the brain was analyzed using real-time PCR. Biochemical assays measured antioxidant enzyme activities, malondialdehyde levels, and total antioxidant capacity in brain tissue and serum. A bioinformatics approach, including molecular docking and the construction of a gene interaction network, was also performed. Our data showed decreased expression of antioxidant genes and Nrf2 and Ho-1 regulatory factors in the Parkinson's group, which were significantly restored by N-acetylcysteine and S-methylcysteine treatments. Long non-coding RNAs were elevated in the Parkinson's disease model and reduced by interventions. Antioxidant enzyme activity and oxidative stress markers were significantly improved by N-acetylcysteine, S-methylcysteine, and their combination. Molecular docking suggested stable interactions of these compounds with antioxidant enzymes. The interaction network highlights Nrf2 as a central regulator of antioxidant genes, modulated by specific lncRNAs. Findings support the neuroprotective role of N-acetylcysteine, S-methylcysteine through activation of the Nrf2/Ho-1 pathway, modulation of long non-coding RNAs, and oxidative stress improvement in Parkinson's disease.