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DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis

The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse...

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Autores principales: Yang, Jia-Ying, Shen, Dan-Yang, Wang, Jun, Dai, Jing-Feng, Qin, Xiao-Yan, Hu, Yang, Lan, Rongfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100577/
https://www.ncbi.nlm.nih.gov/pubmed/35571137
http://dx.doi.org/10.3389/fphar.2022.902796
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author Yang, Jia-Ying
Shen, Dan-Yang
Wang, Jun
Dai, Jing-Feng
Qin, Xiao-Yan
Hu, Yang
Lan, Rongfeng
author_facet Yang, Jia-Ying
Shen, Dan-Yang
Wang, Jun
Dai, Jing-Feng
Qin, Xiao-Yan
Hu, Yang
Lan, Rongfeng
author_sort Yang, Jia-Ying
collection PubMed
description The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPβ and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.
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spelling pubmed-91005772022-05-14 DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis Yang, Jia-Ying Shen, Dan-Yang Wang, Jun Dai, Jing-Feng Qin, Xiao-Yan Hu, Yang Lan, Rongfeng Front Pharmacol Pharmacology The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPβ and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs. Frontiers Media S.A. 2022-04-29 /pmc/articles/PMC9100577/ /pubmed/35571137 http://dx.doi.org/10.3389/fphar.2022.902796 Text en Copyright © 2022 Yang, Shen, Wang, Dai, Qin, Hu and Lan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Yang, Jia-Ying
Shen, Dan-Yang
Wang, Jun
Dai, Jing-Feng
Qin, Xiao-Yan
Hu, Yang
Lan, Rongfeng
DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
title DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
title_full DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
title_fullStr DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
title_full_unstemmed DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
title_short DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis
title_sort dapt attenuates cadmium-induced toxicity in mice by inhibiting inflammation and the notch/hes-1 signaling axis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100577/
https://www.ncbi.nlm.nih.gov/pubmed/35571137
http://dx.doi.org/10.3389/fphar.2022.902796
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