Cargando…

Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish

Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory dr...

Descripción completa

Detalles Bibliográficos
Autores principales: Sun, Wenwei, Wang, Meimei, Zhao, Jun, Zhao, Shuang, Zhu, Wenchao, Wu, Xiaoting, Li, Feifei, Liu, Wei, Wang, Zhuo, Gao, Meng, Zhang, Yiyue, Xu, Jin, Zhang, Meijia, Wang, Qiang, Wen, Zilong, Shen, Juan, Zhang, Wenqing, Huang, Zhibin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475106/
https://www.ncbi.nlm.nih.gov/pubmed/37660128
http://dx.doi.org/10.1038/s41467-023-41114-y
_version_ 1785100648703852544
author Sun, Wenwei
Wang, Meimei
Zhao, Jun
Zhao, Shuang
Zhu, Wenchao
Wu, Xiaoting
Li, Feifei
Liu, Wei
Wang, Zhuo
Gao, Meng
Zhang, Yiyue
Xu, Jin
Zhang, Meijia
Wang, Qiang
Wen, Zilong
Shen, Juan
Zhang, Wenqing
Huang, Zhibin
author_facet Sun, Wenwei
Wang, Meimei
Zhao, Jun
Zhao, Shuang
Zhu, Wenchao
Wu, Xiaoting
Li, Feifei
Liu, Wei
Wang, Zhuo
Gao, Meng
Zhang, Yiyue
Xu, Jin
Zhang, Meijia
Wang, Qiang
Wen, Zilong
Shen, Juan
Zhang, Wenqing
Huang, Zhibin
author_sort Sun, Wenwei
collection PubMed
description Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.
format Online
Article
Text
id pubmed-10475106
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-104751062023-09-04 Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish Sun, Wenwei Wang, Meimei Zhao, Jun Zhao, Shuang Zhu, Wenchao Wu, Xiaoting Li, Feifei Liu, Wei Wang, Zhuo Gao, Meng Zhang, Yiyue Xu, Jin Zhang, Meijia Wang, Qiang Wen, Zilong Shen, Juan Zhang, Wenqing Huang, Zhibin Nat Commun Article Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons. Nature Publishing Group UK 2023-09-02 /pmc/articles/PMC10475106/ /pubmed/37660128 http://dx.doi.org/10.1038/s41467-023-41114-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sun, Wenwei
Wang, Meimei
Zhao, Jun
Zhao, Shuang
Zhu, Wenchao
Wu, Xiaoting
Li, Feifei
Liu, Wei
Wang, Zhuo
Gao, Meng
Zhang, Yiyue
Xu, Jin
Zhang, Meijia
Wang, Qiang
Wen, Zilong
Shen, Juan
Zhang, Wenqing
Huang, Zhibin
Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
title Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
title_full Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
title_fullStr Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
title_full_unstemmed Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
title_short Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
title_sort sulindac selectively induces autophagic apoptosis of gabaergic neurons and alters motor behaviour in zebrafish
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475106/
https://www.ncbi.nlm.nih.gov/pubmed/37660128
http://dx.doi.org/10.1038/s41467-023-41114-y
work_keys_str_mv AT sunwenwei sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT wangmeimei sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT zhaojun sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT zhaoshuang sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT zhuwenchao sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT wuxiaoting sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT lifeifei sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT liuwei sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT wangzhuo sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT gaomeng sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT zhangyiyue sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT xujin sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT zhangmeijia sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT wangqiang sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT wenzilong sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT shenjuan sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT zhangwenqing sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish
AT huangzhibin sulindacselectivelyinducesautophagicapoptosisofgabaergicneuronsandaltersmotorbehaviourinzebrafish