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Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel\u2010induced neuropathy. This study presents the glitazone 4\u2010[(<jats:italic>Z<\/jats:italic>)\u2010(2,4\u2010dioxo\u20101,3\u2010thiazolidin\u20105\u2010ylidene)methyl]\u2010<jats:italic>N<\/jats:italic>\u2010phenylbenzene\u2010sulfonamide (TZD\u2010A1) as a partial agonist of peroxisome proliferator\u2010activated receptor \u03b3 (PPAR\u03b3), its toxicological profile and effects on paclitaxel\u2010induced CIPN in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Interactions of TZD\u2010A1 with PPAR\u03b3 were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl\/6 mice) analyses. Effects of TZD\u2010A1 on CIPN were investigated in paclitaxel\u2010injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain\u2010derived neurotrophic factor (BDNF), nuclear factor erythroid 2\u2010related factor 2 (Nrf2) and PPAR\u03b3, were also measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Docking analysis predicted TZD\u2010A1 interactions with PPAR\u03b3 compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD\u2010A1 were shown in silico, in vitro and in vivo. Paclitaxel\u2010injected mice, concomitantly treated with TZD\u2010A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPAR\u03b3 levels, and up\u2010regulating BDNF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>TZD\u2010A1, a partial agonist of PPAR\u03b3, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD\u2010A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16244","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T09:24:30Z","timestamp":1695029070000},"page":"1128-1149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A partial agonist of PPAR\u03b3 prevents paclitaxel\u2010induced peripheral neuropathy in mice, by inhibiting neuroinflammation"],"prefix":"10.1111","volume":"181","author":[{"given":"Larissa","family":"Benvenutti","sequence":"first","affiliation":[{"name":"Postgraduate Program in Pharmaceutical Science Universidade do Vale do Itaja\u00ed (UNIVALI)  Itaja\u00ed Santa Catarina Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fellippe 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