Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels
Abstract
Objective: Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressant-like effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated. Methods: Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants). Results: Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT. Conclusion: These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression.
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RG108 alters stress-induced DNA methylation bidirectionally in the hippocampus and PFC and triggers antidepressant-like effects as demonstrated in the forced swimming test.
“RG108 alters stress-induced DNA methylation bidirectionally in the hippocampus and PFC and triggers antidepressant-like effects as demonstrated in the forced swimming test.402”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [402]
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“402 The therapeutic potential of HDAC inhibitors (HDACis) is suggested because HDACis may augment the ef fi cacy of antipsychotic medications on coadministration.”
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- Authors
- Sales, A. J., & Joca, S. R. L.
- Affiliations
- Universidade de São Paulo (BR)
- Corresponding author
- Joca, Sâmia Regiane Lourenço
- Venue
- Acta Neuropsychiatrica
- Publisher
- Cambridge University Press (CUP)
- Published
- 2015-06-26
- Volume
- 28
- Issue
- 1
- Pages
- 11-22
- ISSN
- 0924-2708 (ISSN-L)
- 1601-5215
- OpenAlex
- W2109258921
- Cited by
- 62
- References
- 63
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 4
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Neuropsychiatrica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- DNA methylation inhibitors, hypomethylating agents, antidepressants, decitabine, RG108, desipramine, fluoxetine, antidepressant-like effects, hippocampus, prefrontal cortex, depression, forced swim test, open field test, locomotor activity
- MeSH terms
- Animals, Antidepressive Agents, Brain, Disease Models, Animal, Hippocampus, Male, Motor Activity, Repressor Proteins, Stress, Psychological, Swimming, Prefrontal Cortex, DNA Methylation, Mice
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