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

BACKGROUND AND PURPOSE: Chemotherapy-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 APPROACH: Interactions 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 RESULTS: Docking 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 IMPLICATIONS: TZD-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.

Safety assessment of Piper cernuum Vell. (Piperaceae) leaves extract: Acute, sub-acute toxicity and genotoxicity studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper cernuum Vell (Piperaceae) is a native species from Atlantic rain forest, popularly known as pariparoba. Its leaves have been commonly used by rural and urban communities from State of São Paulo, Brazil, to treat pain (orally and topically), and hepatic and renal complications. AIM OF THE STUDY: In this study we evaluated the acute and sub-acute toxicity, genotoxicity and mutagenicity of hydroalcoholic extract obtained from P. cernuum leaf using in vivo and in vitro methods. MATERIAL AND METHODS: In the acute toxicity study, mice were orally treated with P. cernuum extract (2000 mg/kg, p.o.). General behavior and mortality were observed for up to 14 days. In the sub-acute toxicity study, P. cernuum extract was given orally as a single administration to the rats at doses of 50 or 250 mg/kg/day, for 28 days. General behavior, body weight, biochemical and hematological parameters, organ coefficients and pathological morphology were analyzed. The P. cernuum mutagenicity was evaluated using mammalian cell micronucleus assay. Additionally, in vitro toxicity profile of the extract was assessed through cytotoxicity, hemolytic activity, and genotoxicity assay. RESULTS: Data from comet assay demonstrates that high concentrations of P. cernuum extract induce genotoxicity. However, no evidence of hemolytic, cytotoxic or mutagenicity activity was found. In addition, the acute and sub-acute toxicity studies did not show significant changes in body weight, general behavior, hematology and biochemical parameters, organ weight and liver and kidney histopathological analysis. CONCLUSIONS: Together, the results herein obtained indicate that P. cernuum leaves extract did not present significant toxicity when administered to male or female rats. Additionally, no significant alteration in hematological, biochemical and morphological parameters were observed. Data obtained in vitro shows that extract did not present cytotoxicity and mutagenicity. However, the extract induces in vitro genotoxicity, but in high concentration. Further studies are necessary to evaluate the safety of long-term exposure to P. cernuum leaves extract added to in vivo genotoxicity.