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Transcriptional modulation of the hippo signaling pathway by drugs used to treat bipolar disorder and schizophrenia

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Version 1 2021-07-09, 08:27
journal contribution
posted on 2024-06-19, 04:04 authored by B Panizzutti, CC Bortolasci, Briana RandallBriana Randall, S Kidnapillai, Timothy ConnorTimothy Connor, Mark RichardsonMark Richardson, TTT Truong, Zoe Liu, G Morris, Laura GrayLaura Gray, Jee Hyun KimJee Hyun Kim, Olivia DeanOlivia Dean, Michael BerkMichael Berk, Ken WalderKen Walder
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.

History

Journal

International Journal of Molecular Sciences

Volume

22

Article number

ARTN 7164

Pagination

1 - 16

Location

Switzerland

Open access

  • Yes

ISSN

1661-6596

eISSN

1422-0067

Language

English

Publication classification

C Journal article, C1 Refereed article in a scholarly journal

Issue

13

Publisher

MDPI