LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent

Neuroinflammation is often accompanied by central nervous system (CNS) injury seen in various CNS diseases, with no specific treatment. Drug repurposing is a strategy of finding new uses for approved or investigational drugs, and can be enabled by the Library of Integrated Network-based Cellular Sig...

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Autores principales:	Dan Luo, Lu Han, Shengqiao Gao, Zhiyong Xiao, Qingru Zhou, Xiaorui Cheng, Yongxiang Zhang, Wenxia Zhou
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neuroinflammation cognitive impairment drug repurposing LINCS dutasteride Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/0f0ec7c7a3e74e4da4530fe66bf26061
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spelling	oai:doaj.org-article:0f0ec7c7a3e74e4da4530fe66bf260612021-11-25T16:56:43ZLINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent10.3390/brainsci111114112076-3425https://doaj.org/article/0f0ec7c7a3e74e4da4530fe66bf260612021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3425/11/11/1411https://doaj.org/toc/2076-3425Neuroinflammation is often accompanied by central nervous system (CNS) injury seen in various CNS diseases, with no specific treatment. Drug repurposing is a strategy of finding new uses for approved or investigational drugs, and can be enabled by the Library of Integrated Network-based Cellular Signatures (LINCS), a large drug perturbation database. In this study, the signatures of Lipopolysaccharide (LPS) were compared with the signatures of compounds contained in the LINCS dataset. To the top 100 compounds obtained, the Quantitative Structure-Activity Relationship (QSAR)-based tool admetSAR was used to identify the top 10 candidate compounds with relatively high blood–brain barrier (BBB) penetration. Furthermore, the seventh-ranked compound, dutasteride, a 5-α-reductase inhibitor, was selected for in vitro and in vivo validation of its anti-neuroinflammation activity. The results showed that dutasteride significantly reduced the levels of IL-6 and TNF-α in the supernatants of LPS-stimulated BV2 cells, and decreased the levels of IL-6 in the hippocampus and plasma, and the number of activated microglia in the brain of LPS administration mice. Furthermore, dutasteride also attenuated the cognitive impairment caused by LPS stimulation in mice. Taken together, this study demonstrates that the LINCS dataset-based drug repurposing strategy is an effective approach, and the predicted candidate, dutasteride, has the potential to ameliorate LPS-induced neuroinflammation and cognitive impairment.Dan LuoLu HanShengqiao GaoZhiyong XiaoQingru ZhouXiaorui ChengYongxiang ZhangWenxia ZhouMDPI AGarticleneuroinflammationcognitive impairmentdrug repurposingLINCSdutasterideNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENBrain Sciences, Vol 11, Iss 1411, p 1411 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neuroinflammation cognitive impairment drug repurposing LINCS dutasteride Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	neuroinflammation cognitive impairment drug repurposing LINCS dutasteride Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Dan Luo Lu Han Shengqiao Gao Zhiyong Xiao Qingru Zhou Xiaorui Cheng Yongxiang Zhang Wenxia Zhou LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent
description	Neuroinflammation is often accompanied by central nervous system (CNS) injury seen in various CNS diseases, with no specific treatment. Drug repurposing is a strategy of finding new uses for approved or investigational drugs, and can be enabled by the Library of Integrated Network-based Cellular Signatures (LINCS), a large drug perturbation database. In this study, the signatures of Lipopolysaccharide (LPS) were compared with the signatures of compounds contained in the LINCS dataset. To the top 100 compounds obtained, the Quantitative Structure-Activity Relationship (QSAR)-based tool admetSAR was used to identify the top 10 candidate compounds with relatively high blood–brain barrier (BBB) penetration. Furthermore, the seventh-ranked compound, dutasteride, a 5-α-reductase inhibitor, was selected for in vitro and in vivo validation of its anti-neuroinflammation activity. The results showed that dutasteride significantly reduced the levels of IL-6 and TNF-α in the supernatants of LPS-stimulated BV2 cells, and decreased the levels of IL-6 in the hippocampus and plasma, and the number of activated microglia in the brain of LPS administration mice. Furthermore, dutasteride also attenuated the cognitive impairment caused by LPS stimulation in mice. Taken together, this study demonstrates that the LINCS dataset-based drug repurposing strategy is an effective approach, and the predicted candidate, dutasteride, has the potential to ameliorate LPS-induced neuroinflammation and cognitive impairment.
format	article
author	Dan Luo Lu Han Shengqiao Gao Zhiyong Xiao Qingru Zhou Xiaorui Cheng Yongxiang Zhang Wenxia Zhou
author_facet	Dan Luo Lu Han Shengqiao Gao Zhiyong Xiao Qingru Zhou Xiaorui Cheng Yongxiang Zhang Wenxia Zhou
author_sort	Dan Luo
title	LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent
title_short	LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent
title_full	LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent
title_fullStr	LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent
title_full_unstemmed	LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent
title_sort	lincs dataset-based repositioning of dutasteride as an anti-neuroinflammation agent
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0f0ec7c7a3e74e4da4530fe66bf26061
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LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent

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