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In Parkinson's disease (PD), the most common \u03b1\u2010synucleinopathy, the progression of motor and nonmotor deficits, and dopaminergic neuron loss, are closely linked to the spreading of misfolded \u03b1\u2010synuclein. Pioglitazone, a PPAR\u03b3 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 \u03b1\u2010synucleinopathy. Here, we evaluate the safety and neuroprotective effects of four pioglitazone treatment regimens in an \u03b1\u2010synucleinopathy model induced by a single supranigral administration of \u03b2\u2010sitosterol \u03b2\u2010D\u2010glucoside (BSSG), which replicates motor and non\u2010motor symptoms and dopaminergic neurodegeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Adult male Wistar rats were randomly assigned to untreated, mock, \u03b1\u2010synucleinopathy (\u03b1SN), and four pioglitazone treatment groups with distinct dosing schedules. Behavioural assessments, including sensorimotor, motor performance, anxiety\u2010like behaviour, learning, and memory, were conducted at three time points over a 31\u2010day protocol. Histological analyses included quantification of TH+ dopaminergic neurons, Nissl\u2010stained viable neurons, and \u03b1\u2010synuclein aggregates in the substantia nigra pars compacta (SNpc).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Administration of pioglitazone was well tolerated. The pioglitazone regimen, which combines prophylactic and twice\u2010weekly postinduction doses, most effectively attenuated behavioural deficits. Histologically, a significant reduction in \u03b1\u2010synuclein aggregates and preservation of dopaminergic phenotype were demonstrated in the SNpc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Pioglitazone exhibited potential neuroprotective effects in a progressive \u03b1SN model, particularly under a prophylactic plus sustained treatment scheme. These findings support pioglitazone as a promising modifying therapy for PD and \u03b1\u2010synucleinopathies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70431","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T09:11:16Z","timestamp":1777108276000},"page":"4227-4245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Schedule\u2010dependent neuroprotection by pioglitazone in a novel model of \u03b1\u2010synucleinopathy in rats: Integrated behavioural and histological outcomes"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2894-7477","authenticated-orcid":false,"given":"Alberto","family":"Santiago\u2010Balmaseda","sequence":"first","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Neurociencias y Enfermedades Neurodegenerativas (LINEN), Carrera de M\u00e9dico Cirujano, Facultad de Estudios Superiores Iztacala 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