In a BSSG-induced rat α-synucleinopathy model, prophylactic plus twice-weekly postinduction pioglitazone was well tolerated and most effectively reduced α-synuclein aggregates, preserved SNpc dopaminergic phenotype, and attenuated behavioural deficits.

Provides actionable preclinical evidence for repurposing the PPARγ agonist pioglitazone as a schedule-dependent, potentially disease-modifying therapy for PD by linking a specific dosing regimen to aggregate reduction and neuroprotection, justifying further mechanistic and translational studies.

BACKGROUND AND PURPOSE: α-Synucleinopathies are neurodegenerative disorders characterized by the aggregation and propagation of misfolded α-synuclein. In Parkinson's disease (PD), the most common α-synucleinopathy, the progression of motor and nonmotor deficits, and dopaminergic neuron loss, are closely linked to the spreading of misfolded α-synuclein. Pioglitazone, a PPARγ agonist, has shown neuroprotective effects in preclinical models. However, its dosing and its effects on behaviour and neuropathology have not been explored in a model of α-synucleinopathy. Here, we evaluate the safety and neuroprotective effects of four pioglitazone treatment regimens in an α-synucleinopathy model induced by a single supranigral administration of β-sitosterol β-D-glucoside (BSSG), which replicates motor and non-motor symptoms and dopaminergic neurodegeneration. EXPERIMENTAL APPROACH: Adult male Wistar rats were randomly assigned to untreated, mock, α-synucleinopathy (αSN), and four pioglitazone treatment groups with distinct dosing schedules. Behavioural assessments, including sensorimotor, motor performance, anxiety-like behaviour, learning, and memory, were conducted at three time points over a 31-day protocol. Histological analyses included quantification of TH+ dopaminergic neurons, Nissl-stained viable neurons, and α-synuclein aggregates in the substantia nigra pars compacta (SNpc). KEY RESULTS: Administration of pioglitazone was well tolerated. The pioglitazone regimen, which combines prophylactic and twice-weekly postinduction doses, most effectively attenuated behavioural deficits. Histologically, a significant reduction in α-synuclein aggregates and preservation of dopaminergic phenotype were demonstrated in the SNpc. CONCLUSION AND IMPLICATIONS: Pioglitazone exhibited potential neuroprotective effects in a progressive αSN model, particularly under a prophylactic plus sustained treatment scheme. These findings support pioglitazone as a promising modifying therapy for PD and α-synucleinopathies.