New avenues for developing personalized treatments for schizophrenia

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Antibody capture [35S]GTPγS binding scintillation proximity assay (SPA). Credit: Nature communication (2024). DOI: 10.1038/s41467-024-48196-2

An international study, published in Nature communication, could facilitate the creation of new personalized treatments for people diagnosed with schizophrenia. These are patients who suffer from different types of symptoms, such as delusions, hallucinations, cognitive disorders, memory or language disorders and depressive symptoms.

Current treatments, which are largely aimed at a specific therapeutic target, the type 2A serotonin receptor, do not allow selective action on the symptoms experienced by the patient, causing, among other things, side effects and metabolic or motor problems that lead to the treatment is stopped.

In this context, the study has identified the role of certain proteins, the G proteins, which play a crucial role in modulating cell responses in schizophrenia. Specifically, it was shown that two types of these proteins allow the modulation of the main symptoms of this condition.

The study was led by the Hospital del Mar Medical Research Institute, in collaboration with researchers from the Neuropsychopharmacology Group of the University of the Basque Country (UPV/EHU) and researchers from the CIBER of Mental Health (CIBERSAM).

Dr. Jana Selent, one of the main authors of the study and coordinator of the Drug Discovery Group based on G protein-coupled receptors at the Hospital del Mar Medical Research Institute, says: “These proteins are linked to the same receptor, but they work not in the same way and cause diverse reactions in the cells, which gives us very valuable information for future studies that will allow the development of drugs to treat schizophrenia in a personalized way, tailored to the symptoms of each patient.”

High complexity research

To reach these conclusions, the researchers had to conduct complex research. The starting point was to select several available molecules, even if they are not approved drugs for humans, to analyze at the molecular level and through atomic level simulations their ability to interact with the type 2A serotonin receptor. This allowed the selection of four compounds, which were first studied in cells, where they were shown to trigger responses in different types of G proteins when binding to the receptor.

These results were applied to analyzes of human brain tissue samples from the collection of the Neuropsychopharmacology Group of the University of the Basque Country (UPV/EHU). In these studies, it was observed that “the compounds had very different activity with respect to the G proteins: some activated them, but others deactivated them,” explains Dr. Patricia Robledo, also lead author of the study and researcher at the Integrated Pharmacology and Systems Neuroscience Group.

In this regard, “the possibility of inhibiting the coupling of the serotonin 2A receptor to certain G proteins has been proposed as an area of ​​interest for the design of a new type of drug, known as inverse agonists, as potential tools against psychotic disorders,” notes on. Rebeca Diez-Alarcia, first co-author of the article and researcher at UPV/EHU.

Furthermore, in a mouse model designed to simulate schizophrenia symptoms, these compounds had specific behavioral effects depending on which G protein they activated. So, using pharmacological and genetic techniques in mice, it was discovered that one of these G proteins is involved in symptoms related to psychosis, and another type of G protein is involved in cognitive deficits.

Dr. Robledo says, “This is the first time that promising therapeutic targets have been identified for developing drugs that benefit a specific profile of schizophrenia patients.”

Although the compounds used in the study are not yet approved drugs for human use, Dr. Jana Selent that “this multi-scale work reveals a plan for the chemical design of future drugs that target more specific pathways to treat schizophrenia, while avoiding pathways associated with it.” with side effects, which is of great importance for a more personalized treatment.”

Dr. Daniel Berge, a psychiatrist at the Mental Health Institute of the Hospital, who did not participate in the work, points out that “this study will help design more selective drugs for the treatment of schizophrenia, which can provide better tolerance and higher precision. about the symptoms of the disease. All this would promote better treatment compliance, which is essential to prevent relapse and achieve a better quality of life.”

More information:
Elk Kossatz et al., G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory impairment, Nature communication (2024). DOI: 10.1038/s41467-024-48196-2

Provided by IMIM (Hospital del Mar Medical Research Institute)

Quote: New Avenues for Developing Personalized Treatments for Schizophrenia (2024, May 30), retrieved May 31, 2024 from https://medicalxpress.com/news/2024-05-avenues-personalized-treatments-schizophrenia.html

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