Preclinical Parkinson's Disease Models for Non-Motor Symptoms: Research Recommendations from a Systematic Review

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor impairments resulting from dopaminergic neuron degeneration in the substantia nigra. However, PD is increasingly recognized as a multisystem disorder, where non-motor symptoms such as cognitive impairment, mood disturbances, sleep disorders, and autonomic dysfunction significantly impact patients' quality of life. These non-motor symptoms often exhibit poor responsiveness to traditional dopaminergic therapies, underscoring a critical gap in current treatment strategies. Our systematic review investigates established methods of PD induction in rodent models and evaluates the methodologies used to assess non-motor symptoms. The review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Cochrane handbook. Thirty-two studies from 832 articles were included. The studies were characterized by MPTP, 6-OHDA, and rotenone. Our results indicate that there was considerable heterogeneity in behavioral and motor tests, which poses challenges for data comparability and highlights the lack of consensus regarding the most appropriate modeling strategies for specific PD-related behavioral outcomes. All three models demonstrated behavioral changes consistent with dopaminergic impairment when compared to control groups. MPTP-induced models showed significant non-motor deficits across various tests, except in social recognition and novelty-suppressed feeding. The 6-OHDA model consistently produced non-motor impairments, supporting its utility in replicating PD-like neurotoxicity. Rotenone-treated animals exhibited reduced social interaction, decreased sucrose preference, and increased immobility in behavioral assays, further supporting its validity. Overall, our findings indicate that these neurotoxin-based models are effective in reproducing non-motor symptoms of PD, though methodological heterogeneity highlights the need for greater standardization in future preclinical research.