A partial agonist of PPARγ prevents paclitaxel‐induced peripheral neuropathy in mice, by inhibiting neuroinflammation

Abstract

Background and PurposeChemotherapy‐induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30‐50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel‐induced neuropathy. This study presents the glitazone 4‐[(Z)‐(2,4‐dioxo‐1,3‐thiazolidin‐5‐ylidene)methyl]‐N‐phenylbenzene‐sulfonamide (TZD‐A1) as a partial agonist of peroxisome proliferator‐activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel‐induced CIPN in mice.Experimental ApproachInteractions of TZD‐A1 with PPARγ 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‐A1 on CIPN were investigated in paclitaxel‐injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain‐derived neurotrophic factor (BDNF), nuclear factor erythroid 2‐related factor 2 (Nrf2) and PPARγ, were also measured.Key ResultsDocking analysis predicted TZD‐A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD‐A1 were shown in silico, in vitro and in vivo. Paclitaxel‐injected mice, concomitantly treated with TZD‐A1 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 PPARγ levels, and up‐regulating BDNF.Conclusion and ImplicationsTZD‐A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD‐A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.