Schedule-dependent neuroprotection by pioglitazone in a novel model of α-synucleinopathy in rats: Integrated behavioural and histological outcomes.
Schedule-dependent neuroprotection by pioglitazone in a novel model of α-synucleinopathy in rats: Integrated behavioural and histological outcomes.
Where did the research take place?
Possible study sites were matched from the text; these need review.
Time, NO · Possible study site
Behavioural assessments, including sensorimotor, motor performance, anxiety-like behaviour, learning, and memory, were conducted at three time points over a 31-day protocol.Location evidence
Tlalnepantla, MX · Author affiliation
Laboratorio de Investigación en Neurociencias y Enfermedades Neurodegenerativas (LINEN), Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico.Location evidence
MX · Author affiliation · country only
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico.Location evidence
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Original abstract
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.