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The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol
CONTEXT: Resveratrol has shown anti-stress and anti-depressant-like abilities involved in inhibiting phosphodiesterase-4 (PDE4) enzyme. However, its application is limited due to its low efficacy, bioavailability and selectivity. OBJECTIVE: This study synthesized a new resveratrol derivative RES003...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049461/ https://www.ncbi.nlm.nih.gov/pubmed/33847209 http://dx.doi.org/10.1080/13880209.2021.1907422 |
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author | Yu, Yingcong Wang, Jinhui Huang, Xianfeng |
author_facet | Yu, Yingcong Wang, Jinhui Huang, Xianfeng |
author_sort | Yu, Yingcong |
collection | PubMed |
description | CONTEXT: Resveratrol has shown anti-stress and anti-depressant-like abilities involved in inhibiting phosphodiesterase-4 (PDE4) enzyme. However, its application is limited due to its low efficacy, bioavailability and selectivity. OBJECTIVE: This study synthesized a new resveratrol derivative RES003 and evaluated its PDE4 inhibitory and anti-depressant-like activities in vitro and in vivo, respectively. MATERIALS AND METHODS: PDEs inhibitory activities were evaluated by radioactive tracer method. Anti-depressant-like activities of novel resveratrol analogue (RES003) at doses of 2.5, 5.0 and 10 mg/kg was investigated by sugar water consumption and forced swimming tests using male ICR mice under chronic unpredictable stress procedure for 10 days. A total of 84 mice were randomly distributed into seven groups (n = 12). Drugs and vehicle were administered (intra-gastric or intra-peritoneal) once a day from the first to the last day. The molecular mechanisms were identified by western blot. RESULTS: RES003 showed more potent PDE4 inhibitory activity (half maximal inhibitory concentration (IC(50)), 0.87 μM) and better selectivity than resveratrol (IC(50), 18.8 μM). RES003 could significantly increase the consumption of sugar water (p < 0.01) and immobility time (p < 0.01) compared to vehicle-treated stressed groups at doses of 5 and 10 mg/kg. Furthermore, RES003 could significantly increase the levels of cyclic adenosine monophosphate response element binding protein phosphorylation (10 mg/kg, p < 0.05) and brain-derived neurotrophic factor (BDNF) expression (5 and 10 mg/kg, p < 0.05 and 0.01) in mouse brain. DISCUSSION AND CONCLUSIONS: RES003 could ameliorate chronic stress induced depression-like behaviours through inhibition of PDE4 and activation of cAMP-triggered phosphorylation of cAMP response element binding protein/BDNF signalling pathway. Consequently, RES003 is a promising lead compound for the treatment of depression. |
format | Online Article Text |
id | pubmed-8049461 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-80494612021-04-26 The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol Yu, Yingcong Wang, Jinhui Huang, Xianfeng Pharm Biol Research Article CONTEXT: Resveratrol has shown anti-stress and anti-depressant-like abilities involved in inhibiting phosphodiesterase-4 (PDE4) enzyme. However, its application is limited due to its low efficacy, bioavailability and selectivity. OBJECTIVE: This study synthesized a new resveratrol derivative RES003 and evaluated its PDE4 inhibitory and anti-depressant-like activities in vitro and in vivo, respectively. MATERIALS AND METHODS: PDEs inhibitory activities were evaluated by radioactive tracer method. Anti-depressant-like activities of novel resveratrol analogue (RES003) at doses of 2.5, 5.0 and 10 mg/kg was investigated by sugar water consumption and forced swimming tests using male ICR mice under chronic unpredictable stress procedure for 10 days. A total of 84 mice were randomly distributed into seven groups (n = 12). Drugs and vehicle were administered (intra-gastric or intra-peritoneal) once a day from the first to the last day. The molecular mechanisms were identified by western blot. RESULTS: RES003 showed more potent PDE4 inhibitory activity (half maximal inhibitory concentration (IC(50)), 0.87 μM) and better selectivity than resveratrol (IC(50), 18.8 μM). RES003 could significantly increase the consumption of sugar water (p < 0.01) and immobility time (p < 0.01) compared to vehicle-treated stressed groups at doses of 5 and 10 mg/kg. Furthermore, RES003 could significantly increase the levels of cyclic adenosine monophosphate response element binding protein phosphorylation (10 mg/kg, p < 0.05) and brain-derived neurotrophic factor (BDNF) expression (5 and 10 mg/kg, p < 0.05 and 0.01) in mouse brain. DISCUSSION AND CONCLUSIONS: RES003 could ameliorate chronic stress induced depression-like behaviours through inhibition of PDE4 and activation of cAMP-triggered phosphorylation of cAMP response element binding protein/BDNF signalling pathway. Consequently, RES003 is a promising lead compound for the treatment of depression. Taylor & Francis 2021-04-13 /pmc/articles/PMC8049461/ /pubmed/33847209 http://dx.doi.org/10.1080/13880209.2021.1907422 Text en © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Yu, Yingcong Wang, Jinhui Huang, Xianfeng The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol |
title | The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol |
title_full | The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol |
title_fullStr | The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol |
title_full_unstemmed | The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol |
title_short | The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol |
title_sort | anti-depressant effects of a novel pde4 inhibitor derived from resveratrol |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049461/ https://www.ncbi.nlm.nih.gov/pubmed/33847209 http://dx.doi.org/10.1080/13880209.2021.1907422 |
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