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Article

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

1
Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, IMPACT, Geelong 3220, Australia
2
Genomics Centre, School of Life and Environmental Sciences, Deakin University, Burwood 3125, Australia
3
Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville 3052, Australia
4
Department of Psychiatry, Royal Melbourne Hospital, University of Melbourne, Parkville 3052, Australia
5
Centre of Youth Mental Health, University of Melbourne, Parkville 3052, Australia
6
Orygen Youth Health Research Centre, Parkville 3052, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Juan F. Lopez-Gimenez
Int. J. Mol. Sci. 2021, 22(13), 7164; https://doi.org/10.3390/ijms22137164
Received: 21 June 2021 / Revised: 26 June 2021 / Accepted: 28 June 2021 / Published: 2 July 2021
(This article belongs to the Special Issue Molecular Mechanisms of Schizophrenia and Novel Targets)
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. View Full-Text
Keywords: Hippo pathway; psychotropic drugs; bipolar disorder; schizophrenia; inflammation; drug repurposing; connectivity map; psychiatry; neuroscience Hippo pathway; psychotropic drugs; bipolar disorder; schizophrenia; inflammation; drug repurposing; connectivity map; psychiatry; neuroscience
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MDPI and ACS Style

Panizzutti, B.; Bortolasci, C.C.; Spolding, B.; Kidnapillai, S.; Connor, T.; Richardson, M.F.; Truong, T.T.T.; Liu, Z.S.J.; Morris, G.; Gray, L.; Hyun Kim, J.; Dean, O.M.; Berk, M.; Walder, K. Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia. Int. J. Mol. Sci. 2021, 22, 7164. https://doi.org/10.3390/ijms22137164

AMA Style

Panizzutti B, Bortolasci CC, Spolding B, Kidnapillai S, Connor T, Richardson MF, Truong TTT, Liu ZSJ, Morris G, Gray L, Hyun Kim J, Dean OM, Berk M, Walder K. Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia. International Journal of Molecular Sciences. 2021; 22(13):7164. https://doi.org/10.3390/ijms22137164

Chicago/Turabian Style

Panizzutti, Bruna, 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, and Ken Walder. 2021. "Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia" International Journal of Molecular Sciences 22, no. 13: 7164. https://doi.org/10.3390/ijms22137164

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