Pramipexole alleviates non-motor symptoms and autophagy-related protein abnormalities in a dual neurotoxin Parkinson's disease model.

Parkinson's disease (PD) is characterized by motor deficits and debilitating non-motor symptoms (NMS), including depression, anxiety, and cognitive impairment. While current therapies alleviate motor dysfunction, NMS management remains a critical unmet need. Pramipexole (PPX), a non-ergoline dopamine agonist with high selectivity for D2/D3 receptors (particularly D3), demonstrates potential for multi-target modulation beyond motor improvement. To systematically evaluate the efficacy of PPX against NMS and elucidate its novel mechanism involving autophagy regulation, a dual neurotoxin-induced PD mouse model (MPTP and DSP-4; MPTP:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; DSP-4: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) recapitulating both motor and NMS was employed. PPX significantly improved NMS, reducing anxiety/depressive -like behavior and cognitive decline, alongside restoring motor function. Moreover, PPX administration promoted survival of dopaminergic and noradrenergic neurons and preserved synaptic integrity in a double lesion model of PD. In our molecular detection, PPX treatment was accompanied by enhanced key components of autophagy (Beclin-1/P62) and rectified deficient mitophagy (BNIP3L/PINK1/Parkin). This study identifies PPX as a dual-action therapeutic that concurrently alleviates motor/NMS in PD model mice, and this therapeutic effect may be associated with altered expression of autophagy-related proteins.