A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation
© 2023 British Pharmacological Society..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:181 |
---|---|
Enthalten in: |
British journal of pharmacology - 181(2024), 7 vom: 11. März, Seite 1128-1149 |
Sprache: |
Englisch |
---|
Links: |
---|
Themen: |
Brain-Derived Neurotrophic Factor |
---|
Anmerkungen: |
Date Completed 12.03.2024 Date Revised 12.03.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1111/bph.16244 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM362179417 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM362179417 | ||
003 | DE-627 | ||
005 | 20240312233230.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1111/bph.16244 |2 doi | |
028 | 5 | 2 | |a pubmed24n1324.xml |
035 | |a (DE-627)NLM362179417 | ||
035 | |a (NLM)37721089 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Benvenutti, Larissa |e verfasserin |4 aut | |
245 | 1 | 2 | |a A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 12.03.2024 | ||
500 | |a Date Revised 12.03.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2023 British Pharmacological Society. | ||
520 | |a 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 | ||
520 | |a 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 | ||
520 | |a 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 | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a chemotherapy | |
650 | 4 | |a chronic pain | |
650 | 4 | |a glitazone | |
650 | 4 | |a mice | |
650 | 4 | |a neuroinflammation | |
650 | 4 | |a taxane | |
650 | 7 | |a Paclitaxel |2 NLM | |
650 | 7 | |a P88XT4IS4D |2 NLM | |
650 | 7 | |a PPAR gamma |2 NLM | |
650 | 7 | |a Brain-Derived Neurotrophic Factor |2 NLM | |
650 | 7 | |a NF-E2-Related Factor 2 |2 NLM | |
700 | 1 | |a Wolff, Fellippe Ramos |e verfasserin |4 aut | |
700 | 1 | |a Corrêa, Thiago Patrício |e verfasserin |4 aut | |
700 | 1 | |a Melato, Jessica |e verfasserin |4 aut | |
700 | 1 | |a Goldoni, Fernanda Capitanio |e verfasserin |4 aut | |
700 | 1 | |a De Faveri, Renata |e verfasserin |4 aut | |
700 | 1 | |a Patel, Yasmin Beatrisse Klein |e verfasserin |4 aut | |
700 | 1 | |a de Souza, Jade André |e verfasserin |4 aut | |
700 | 1 | |a Grockoski, Heloise Adeli |e verfasserin |4 aut | |
700 | 1 | |a Nilz, Paulo Mateus |e verfasserin |4 aut | |
700 | 1 | |a Bombardelli, Cleber Luiz |e verfasserin |4 aut | |
700 | 1 | |a Remor, Aline Pertile |e verfasserin |4 aut | |
700 | 1 | |a Varela, Karina Giacomini |e verfasserin |4 aut | |
700 | 1 | |a Costa, Natáli Tereza Capistrano |e verfasserin |4 aut | |
700 | 1 | |a Hernandes, Marcelo Zaldini |e verfasserin |4 aut | |
700 | 1 | |a Lacerda, Mariella Guimarães |e verfasserin |4 aut | |
700 | 1 | |a Rodrigues, Kathlen Deruci |e verfasserin |4 aut | |
700 | 1 | |a Milton, Flora Aparecida |e verfasserin |4 aut | |
700 | 1 | |a Neves, Francisco de Assis Rocha |e verfasserin |4 aut | |
700 | 1 | |a Pereira, Maria Eduarda Signorini |e verfasserin |4 aut | |
700 | 1 | |a Kormann Imianowsky, Elaine Cristina |e verfasserin |4 aut | |
700 | 1 | |a de Campos Buzzi, Fátima |e verfasserin |4 aut | |
700 | 1 | |a Brunaldi Marutani, Victor Hugo |e verfasserin |4 aut | |
700 | 1 | |a Stoeberl, Luis Carlos |e verfasserin |4 aut | |
700 | 1 | |a Correa, Rogério |e verfasserin |4 aut | |
700 | 1 | |a Eller, Sarah |e verfasserin |4 aut | |
700 | 1 | |a de Oliveira, Tiago Franco |e verfasserin |4 aut | |
700 | 1 | |a Gonçalves, Thamires Bragança Paduam |e verfasserin |4 aut | |
700 | 1 | |a da Silva, Raquel Costa |e verfasserin |4 aut | |
700 | 1 | |a Passos, Giselle Fazzioni |e verfasserin |4 aut | |
700 | 1 | |a da Costa, Robson |e verfasserin |4 aut | |
700 | 1 | |a Santin, José Roberto |e verfasserin |4 aut | |
700 | 1 | |a Quintão, Nara Lins Meira |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t British journal of pharmacology |d 1968 |g 181(2024), 7 vom: 11. März, Seite 1128-1149 |w (DE-627)NLM000001325 |x 1476-5381 |7 nnns |
773 | 1 | 8 | |g volume:181 |g year:2024 |g number:7 |g day:11 |g month:03 |g pages:1128-1149 |
856 | 4 | 0 | |u http://dx.doi.org/10.1111/bph.16244 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 181 |j 2024 |e 7 |b 11 |c 03 |h 1128-1149 |