Introduction: Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the nigrostriatal pathway, primarily due to misfolded α-synuclein. Lysosomes play a crucial role in degrading these proteins through cathepsins, a mechanism impaired in PD. Trigonelline (TGN), an alkaloid found in plants and identified in jellyfish by our research group, has been shown to inhibit caspase-1. Its analog, nicotinic acid, has demonstrated beneficial effects in PD models. This study investigates the modulation of cathepsin D (CTSD) and cathepsin B (CTSB) activity using TGN in the substantia nigra (SN) and caudate putamen (CPu) of PD-induced rats. Methods: Male Wistar rats were divided into three groups: Control (striatal saline injection and oral vehicle), PD (striatal 6-OHDA and oral vehicle), and PD and TGN (striatal 6-OHDA and oral TGN treatment). Fourteen days after striatal injections, animals were treated with TGN (50 mg/Kg; once daily for five consecutive days). One hour after the final treatment, the animals were euthanized, and the SN and CPu were collected for enzymatic activity analysis using specific substrates. Fluorescence was measured every minutes over a 50-minute period. Results: Preliminary findings indicate that in the PD model, CTSD activity in the right SN was reduced (Control = 1.65 AUF/min; PD = 0.14 AUF/min), as was CTSB activity (Control = 2.37 AUF/min; PD = 1.37 AUF/min). TGN treatment enhanced the activity of both enzymes (CTSD = 0.79 AUF/min; CTSB = 3.07 AUF/min). In the CPu, CTSD activity remained similar among groups, whereas CTSB activity was reduced in PD but was not restored by TGN. Conclusion: TGN enhances the activity of key lysosomal enzymes in the SN, which is associated with the removal of protein aggregates. These findings suggest a potential role for TGN in maintaining lysosomal functionality in this critical brain region affected by PD.