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Molecular signaling pathways underlying schizophrenia

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journal contribution
posted on 02.08.2021, 06:50 by J Tiihonen, M Koskuvi, M Lähteenvuo, K Trontti, I Ojansuu, O Vaurio, TD Cannon, J Lönnqvist, S Therman, J Suvisaari, Lesley SimLesley Sim, A Tanskanen, H Taipale, Š Lehtonen, J Koistinaho
The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA–related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists – which have shown beneficial effects in an experimental Adcyap1−/− mouse model for schizophrenia – could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.

Funding

The study was partially funded by the Ministry of Social Affairs and Health, Finland, through the developmental fund for Niuvanniemi Hospital, Business Finland, Sigrid Juselius Foundation, the University of Helsinki, and the University of Eastern Finland.

History

Publication Date

01/06/2021

Journal

Schizophrenia Research

Volume

232

Pagination

33-41

Publisher

Elsevier

ISSN

0920-9964

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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