Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were trea...

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Bibliographic Details
Main Authors: Bruna Panizzutti, Chiara C. Bortolasci, Briana Spolding, Srisaiyini Kidnapillai, Timothy Connor, Mark F. Richardson, Trang T. T. Truong, Zoe S. J. Liu, Gerwyn Morris, Laura Gray, Jee Hyun Kim, Olivia M. Dean, Michael Berk, Ken Walder
Format: Article
Language:English
Published: MDPI AG 2021-07-01
Series:International Journal of Molecular Sciences
Subjects:
Hippo pathway
psychotropic drugs
bipolar disorder
schizophrenia
inflammation
drug repurposing
Online Access:https://www.mdpi.com/1422-0067/22/13/7164
Description
Summary:Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.
ISSN:1661-6596
1422-0067

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