Selecting preclinical models of parkinson's disease in drug development: Criteria and limitations

Parkinson's disease encompasses several interrelated pathological processes, including impaired dopaminergic neurotransmission, mitochondrial dysfunction, protein aggregation, and neuroinflammation. The suitability of a preclinical model is therefore determined not by its popularity but by how well it addresses a specific research question. No single model reproduces the full range of motor, non-motor, and morphological features of the disease [1, 2]. Pharmacological models based on dopamine receptor antagonists are useful for studying reversible motor impairment and for initial identification of functional effects. However, they cannot serve as standalone evidence of neuroprotection, as they do not necessarily cause progressive loss of dopaminergic neurons. Neurotoxin-based models, including 6-hydroxydopamine-, MPTP-, and rotenone-induced paradigms, can be used to investigate selected aspects of neuronal injury, but differ in their mechanisms, selectivity, severity of systemic effects, and reproducibility [3]. Genetic and α-synuclein-oriented models broaden opportunities to investigate specific molecular pathways, while cell systems based on human induced pluripotent stem cells help explore individual and species-specific features. Their use also has limitations: cell cultures do not fully capture interactions among neurons, glia, the vascular system, and immune mechanisms. Thus, the use of multiple models should be functionally justified rather than merely formal. When interpreting behavioural tests, alternative explanations for changes in activity must be ruled out, including sedation, general toxicity, and effects on anxiety or motivation. To support a robust conclusion, behavioural outcomes should be compared with pharmacokinetic, biochemical, and, where possible, morphological measures. Methodological reliability also depends on randomisation, blinding, prespecified endpoints, and transparent reporting of results. Accordingly, the development of novel antiparkinsonian agents should rely on the sequential use of complementary models: initial functional screening, confirmation of the mechanism, assessment of tolerability and exposure, and subsequent testing of the hypothesis in a model appropriate to the proposed pathological process. This workflow helps define the limits of each conclusion and reduces the risk of extrapolating a local effect to the complexity of human disease.