Pramipexole enhances levodopa's therapeutic efficacy in Parkinson's disease: Role of glutaredoxin-1 (GRX1), peroxiredoxin3 (PRX3), thioredoxin (TRX), 8-hydroxy-2 -deoxyguanosine (8-OHDG), and neurosteroid dehydroepiandrosterone sulfate (DHEA-S).

BACKGROUND: Parkinson's disease (PD) is characterised byprogressive neurodegeneration and dopamine deficiency.Levodopa remains a cornerstone treatment, but its longterm use is associated with motor complications andreduced efficacy. This study investigates the clinical benefits of combining pramipexole with Levodopa in PDpatients, focusing on improvements in oxidative stress,cognitive function, and motor control. Additionally, thestudy explores the role of novel biomarkers, includingglutaredoxin-1 (Grx1), peroxiredoxin-3 (Prx3), thioredoxin(Trx), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and neurosteroid dehydroepiandrosterone sulfate (DHEA-S), inevaluating oxidative stress and neuroprotection. METHODS: A total of 92 PD patients were enrolled andassigned to either a levodopa monotherapy group (n=46)or a pramipexole-levodopa combination group (n=46).Clinical efficacy was assessed using the Unified Parkinson'sDisease Rating Scale (UPDRS). Cognitive function wasevaluated using the Mini-Mental State Examination(MMSE) and the Montreal Cognitive Assessment (MoCA).Oxidative stress markers (SOD, GSH, GSH-PX, CAT, alongwith Grx1, Prx3, Trx, and 8-OHdG) were measured inserum samples. Additionally, DHEA-S was analysed as aneurosteroid biomarker to assess its potential role in cognitive and motor function improvements. Quality of life(QOL) was evaluated using the PDQ-39 questionnaire. RESULTS: The combination therapy group exhibited a significantly higher effective rate (93.48% ) compared to the levodopa group (78.26% ) (P< 0.05). UPDRS scores were significantly lower in the combination group at 6- and12-week post-treatment (P < 0 .0 5 ). The combinationgroup also showed a significantly lower incidence ofadverse drug reactions (6.52% vs. 23.91% , P< 0.05). After3 months, the combination group displayed significantlyhigher levels of SOD, GSH, GSH-PX, CAT, Grx1, Prx3, andTrx, while 8-OHdG levels were significantly reduced, indicating enhanced neuroprotection and reduced oxidativestress. DHEA-S levels were also elevated, correlating withimproved MMSE and M oCA scores (P < 0 .0 5 ). Theobserved DHEA-S elevation in the combination group maybe due to pramipexole's dopaminergic modulation ofhypothalamic-pituitary-adrenal axis activity, potentiallyenhancing adrenal steroidogenesis. Alternatively, improvements in motor and cognitive function may reduce chronicstress, indirectly elevating DHEA-S. It suggests a neurosteroid-mediated cognitive benefit. QOL was significantlybetter in the combination group after 3 months of intervention (P< 0.05). CONCLUSIONS: Pramipexole combined with Levodopa significantly improves clinical outcomes, reduces adverse effects,enhances cognitive function, and alleviates oxidative stressin PD patients. The inclusion of novel biomarkers such asGrx1, Prx3, Trx, 8-OHdG, and DHEA-S provides deeperinsight into the molecular mechanisms underlying thesetherapeutic effects. This combination therapy represents avaluable strategy for improving PD management and warrants wider clinical application.