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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Brain Sciences |
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| Online Access: | https://www.mdpi.com/2076-3425/11/11/1411 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:38:57Z |
| format | Article |
| id | doaj.art-0f0ec7c7a3e74e4da4530fe66bf26061 |
| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-10T05:38:57Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Brain Sciences |
| spelling | doaj.art-0f0ec7c7a3e74e4da4530fe66bf260612023-11-22T22:37:16ZengMDPI AGBrain Sciences2076-34252021-10-011111141110.3390/brainsci11111411LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation AgentDan Luo0Lu Han1Shengqiao Gao2Zhiyong Xiao3Qingru Zhou4Xiaorui Cheng5Yongxiang Zhang6Wenxia Zhou7Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNeuroinflammation 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.https://www.mdpi.com/2076-3425/11/11/1411neuroinflammationcognitive impairmentdrug repurposingLINCSdutasteride |
| spellingShingle | 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 Brain Sciences neuroinflammation cognitive impairment drug repurposing LINCS dutasteride |
| title | 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_short | LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent |
| title_sort | lincs dataset based repositioning of dutasteride as an anti neuroinflammation agent |
| topic | neuroinflammation cognitive impairment drug repurposing LINCS dutasteride |
| url | https://www.mdpi.com/2076-3425/11/11/1411 |
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