03:36pm Tuesday 19 November 2019

Describing the mechanism to explain resistance to pharmacological treatment in schizophrenia

The research, published in September by Nature Neuroscience, opens the door to the design and use of new drugs for this devastating chronic illness that affects 1% of the population worldwide.

The researchers aimed to discover what epigenetic changes, i.e. what alterations in the genes due to external factors, were involved in the resistance to treatment with atypical antipsychotic drugs, the most usual in schizophrenia. They discovered that, with time, there is an increase of the HDAC2 enzyme in the brain of schizophrenia patients and this over-expression is responsible for the genetic alterations that cause the lower efficacy of the drugs. That is to say, the medication itself prescribed for treating schizophrenia could be responsible for the resistance to chronic treatment.

The mechanism that scientists discovered after studying post mortem tissue from schizophrenia patients and from animal models. The target of atypical antipsychotic drugs is the 5HT2A receptor of serotonin, a neurotransmitter which is altered in schizophrenia sufferers and which then generates hallucinatory syndromes. Previous research work in which UPV/EHU researchers participated, has shown, however, that the treatment affects another neurotransmitter, glutamate. In concrete, it reduces the mGlu2 receptors of the glutamate neurotransmitter, which increases the so-called negative symptoms of the disease, for example, going into one´s shell and lack of interest. Researchers have now shown what the cause of this disorder is: the increase – triggered by medication – of the activity of the HDAC2 enzyme which, in turn, inhibits the mGlu2 receptor.

“With this current research, the mechanism responsible for these alterations has been unravelled and is important scientific support for the use of medication that stimulates the mGlu2 receptors in treating schizophrenia”, explained UPV/EHU Professor of Pharmacology, Javier Meana. In fact, a number of pharmaceutical companies are currently developing antipsychotic drugs targeting this new objective. The work has also given rise to clinical studies in the USA with HDAC2 enzyme inhibitors, as possible adjunctive treatment to antipsychotic drugs in schizophrenia.

Participating in this research work for the UPV/EHU were lecturers at the Department of Pharmacology Ane Gabilondo, Koldo Callado and Javier Meana and post-doctoral researcher Aintzane García-Bea, whose thesis will form part of the study. The team is part of the Preparation and Research Unit at the UPV/EHU working in Neurochemistry, Neuropsyhcopharmacology and Psychiatry, and is also a member of the Biomedical Net Research Centre for Mental Health (CIBERSAM) and of the Biocruces Institute.

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Internet reference
Bibliographic references: HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Mitsumasa Kurita, Terrell Holloway, Aintzane García-Bea, Alexey Kozlenkov, Allyson K Friedman, José L Moreno, Mitra Heshmati, Sam A Golden, Pamela J Kennedy, Nagahide Takahashi, David M Dietz, Giuseppe Mocci, Ane M Gabilondo, James Hanks, Adrienne Umali, Luis F Callado, Amelia L Gallitano, Rachael L Neve, Li Shen, Joseph D Buxbaum, Ming-Hu Han, Eric J Nestler, J Javier Meana, Scott J Russo & Javier González-Maeso. Nature Neuroscience 15, 1245–1254 (2012) doi:10.1038/nn.3181
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