Esketamine ameliorates post-stroke anxiety by modulating microglial HDAC3/NF-κB/COX1 inflammatory signaling in ischemic cortex

Huang, Angus; Chen, Yang; Wang, Shaoshuang; Du, Hailiang; Guan, Ao; Wu, Huang-Hui; Zhai, Qixiao; Duan, Na; Li, Xuying; Zhao, Peng; Zhu, Yanting; Bai, Jing; Ye, Xiao; Yang, Tingting; Wang, Qiang; Deng, Bin

doi:10.1016/j.ejphar.2023.175667

Cited by 5 publications

(1 citation statement)

References 38 publications

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“…Astrocyte-like glial cells play an important role in information transmission between neurons and glial cells, in addition to guaranteeing neurotransmitter homeostasis by expressing a set of specific transporter proteins such as excitatory amino acid transporter 1 (EAAT1) or GABA transporter (GAT) [ 106 – 108 ]. Previous studies have indicated that drugs can also induce a response in glial cells; for instance, esketamine alleviates cortical microglial activation, alters microglial number, and maintains morphological features in mice [ 109 ]. Moreover, MPH increases Glu uptake in chick cerebellum Bergmann glial cells [ 110 ], and different doses of MPH induce different glial cells (e.g., astrocytes, microglia) under ADHD or non-ADHD conditions in rats [ 111 ].…”

Section: Resultsmentioning

confidence: 99%

The effects of methylphenidate and atomoxetine on Drosophila brain at single-cell resolution and potential drug repurposing for ADHD treatment

Qu,

Zhou,

Wang

et al. 2023

Mol Psychiatry

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The stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) are frequently used for the treatment of attention-deficit/hyperactivity disorder (ADHD); however, the function of these drugs in different types of brain cells and their effects on related genes remain largely unknown. To address these questions, we built a pipeline for the simultaneous examination of the activity behavior and transcriptional responses of Drosophila melanogaster at single-cell resolution following drug treatment. We selected the Drosophila with significantly increased locomotor activities (hyperactivity-like behavior) following the administration of each drug in comparison with the control (same food as the drug-treated groups with 5% sucrose, yeast, and blue food dye solution) using EasyFlyTracker. Subsequently, single cell RNA sequencing (scRNASEQ) was used to capture the transcriptome of 82,917 cells, unsupervised clustering analysis of which yielded 28 primary cell clusters representing the major cell types in adult Drosophila brain. Indeed, both neuronal and glial cells responded to MPH and ATX. Further analysis of differentially expressed genes (DEGs) revealed distinct transcriptional changes associated with these two drugs, such as two well-studied dopamine receptor genes (Dop2R and DopEcR) were responsive to MPH but not to ATX at their optimal doses, in addition to genes involved in dopamine metabolism pathways such as Syt1, Sytalpha, Syt7, and Ih in different cell types. More importantly, MPH also suppressed the expression of genes encoding other neurotransmitter receptors and synaptic signaling molecules in many cell types, especially those for Glu and GABA, while the responsive effects of ATX were much weaker. In addition to monoaminergic neuronal transmitters, other neurotransmitters have also shown a similar pattern with respect to a stronger effect associated with MPH than with ATX. Moreover, we identified four distinct glial cell subtypes responsive to the two drugs and detected a greater number of differentially expressed genes associated with ensheathing and astrocyte-like glia. Furthermore, our study provides a rich resource of candidate target genes, supported by drug set enrichment analysis (P = 2.10E-4; hypergeometric test), for the further exploration of drug repurposing. The whole list of candidates can be found at ADHDrug (http://adhdrug.cibr.ac.cn/). In conclusion, we propose a fast and cost-efficient pipeline to explore the underlying molecular mechanisms of ADHD drug treatment in Drosophila brain at single-cell resolution, which may further facilitate drug repurposing applications.

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