<p>L-dopa-induced dyskinesia (LID) is an incapacitating complication of long-term administration of L-dopa therapy that commonly affects patients with Parkinson’s disease (PD) due to the widespread use of the causative drug. Herein, we investigated the therapeutic potential of sitagliptin, a drug used to treat type 2 diabetes mellitus, to treat LID. 6-hydroxydopamine (6-OHDA) was unilaterally injected into the left side of the substantia nigra pas compacta to induce a mouse model of PD. After four weeks of 6-OHDA induction, L-dopa was administered with or without sitagliptin for 11 consecutive days. LID was monitored using abnormal involuntary movement (AIM) scoring, conducted on days 5 and 10 of L-dopa treatment. Comparative proteomic analysis was performed on the 6-OHDA-lesioned striatum by comparing groups treated with vehicle + L-dopa and sitagliptin + L-dopa. Sitagliptin combined with L-dopa significantly attenuated AIM scores in 6-OHDA-lesioned mice. Proteomic analysis following sitagliptin treatment showed an increase in proteins involved in mitochondrial function regulation and a decrease in proteins associated with cytoskeleton function regulation. Changes in the expression of Ndufb2, a subunit of NADH: ubiquinone oxidoreductase (complex I), and Arc, an immediate early gene (IEG), which showed the most significant increase and decrease, respectively, were validated using western blotting and RT-PCR analysis. These findings suggest that sitagliptin may have therapeutic potential by enhancing mitochondrial functions and suppressing neuronal activity in the striatum, thereby mitigating the incapacitating complications associated with long-term L-dopa use in patients with PD.</p>