Abstract
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.
Highlights
Neuroinflammation is a physiological protective response in the context of infection and injury [1], but is an important factor contributing to cognitive impairment and neurodegenerative diseases when exceeding critical thresholds [2,3,4]
Studies have shown that certain nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the risk of an asymptomatic individual developing neurodegenerative disease, they result in no significant improvement in patients with basic central nervous system (CNS) diseases, and may even worsen the diseases [15]
These results show that dutasteride can effectively attenuate the activation of microglia cells caused by LPS
Summary
Neuroinflammation is a physiological protective response in the context of infection and injury [1], but is an important factor contributing to cognitive impairment and neurodegenerative diseases when exceeding critical thresholds [2,3,4]. Lipopolysaccharide (LPS), a toll-like receptor ligand, commonly induces neuroinflammation [5,6]. A large number of studies have shown that both central and peripheral injection of LPS can induce neuroinflammation and cognitive impairment [6,7,8,9]. The most commonly used anti-inflammatory drugs in clinics are nonsteroidal anti-inflammatory drugs (NSAIDs), which have been identified as potential options for the treatment of neuroinflammation [14]. It is necessary to identify a new therapy for neuroinflammation from the FDA-approved drugs
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