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Researchers of a new study published in the Journal of Molecular Neurobiology investigated the therapeutic potential of drugs that inhibit stress-induced epigenetic changes.

“It is well described in the literature that stress triggers epigenetic modifications which result in changes in the expression of genes that code for proteins important for several functions in the brain, such as neurotransmitter signaling and neuroplasticity,” study author Sâmia Joca told us. “Impaired neuroplasticity and neurotransmitter signaling in limbic brain regions (responsible for emotion, affection, cognition and endocrine control) has been considered central mechanisms involved in depression neurobiology.”

Joca was Associate Professor at the University of Sao Paulo at the time the study was developed and is currently working as Associate Professor at Aarhus University in Denmark.
The research team hypothesized that the pharmacological inhibition of the enzymes that convey epigenetic changes, in this case DNA methylation, could ‘erase’ the aberrant changes in gene expression induced by stress and promote antidepressant effects in animal models.

“We chose this topic because, although effective, the currently available medication to treat depression requires three-four weeks of continuous treatment to promote a significant improvement of depressive symptoms,” Joca told us. “Moreover, a large proportion of patients do not respond (approximately 1/3) or respond only partially to the treatments available (40-50%). Therefore, there is an urgent unmet need to find/develop new drugs that can act faster and also effectively treat patients that do not respond to the available medications.”

Researchers expected that the administration of drugs that inhibit DNA methylation would promote antidepressant effects in different animal models and that this effect would develop faster when compared to conventional monoaminergic antidepressants (ex. Fluoxetine) because it would directly target the mechanisms that control gene expression.

“Moreover,” added Joca, “we expected that the antidepressant effect induced by the drugs would involve epigenetic modification in genes important for the control of neuroplasticity (ex. BDNF).”

Since the modification of DNA methylation is an effect observed after chronic antidepressant treatment, as Joca has shown before, they hypothesized that acute injection of a drug that directly target this epigenetic mechanism could convey fast antidepressant effects. If confirmed, this could point to a new promising mechanism to be explored for drug development and better understanding of depression neurobiology.

To test out their theory, Joca and the team administered drugs that block the enzymes that promove DNA methylation, called DNA methylation inhibitors, in rats submitted to two well validated animal models of depression. After the behavioral experiments, they collected the brain regions of interest from the animals and performed analysis of DNA methylation levels in genes associated to neurotransmitter signaling and neuroplasticity, as well as the expression level of the same genes. They also injected drugs directly into the brain region where they found significant changes (prefrontal cortex) to block neurotrophin signaling and therefore investigate if the behavioral effects induced by DNA methylation inhibitors could be associated to neuroplastic mechanism in this brain region.

“Our results showed that the antidepressant effect could only be observed after repeated treatment with the conventional antidepressant drugs in the model we used (learned helplessness), as showed before, but the drugs that target DNA methylation promoted an antidepressant effect after a single systemic injection, which is suggestive of a fast-acting mechanism,” Joca told us. “We also observed that stress induced increased methylation and decreased the expression of genes associated with neuroplasticity in the prefrontal cortex (BDNF and TrkB).”

As well, the direct administration of drugs that block BDNF signaling in the prefrontal cortex also blocked the antidepressant effect induced by the epigenetic modulators. Altogether, these results indicate that drugs that block DNA methylation can promote rapid antidepressant effects due to their ability to ‘erase’ epigenetic marks induced by stress in genes associated with neuroplasticity in specific brain regions, like the prefrontal cortex.

“It was, indeed, an interesting observation, since we saw the same effect with two different drugs (RG108 and 5-Aza) which are chemically unrelated but only share the ability to block DNA methylation,” Joca told us. “The effect was observed after a single injection, at very small doses. It was also observed in two different animal models which have been widely validated. It was surprising to see that this behavioral effects occurred in association with corresponding molecular changes, but only in one brain region, while other genes investigated were not affected, despite being also regulated by epigenetic mechanisms.”

Joca believes the results open up new possibilities to investigate the regulation of DNA methylation in depression neurobiology and treatment. Joca believes that ultimately, this could lead to a better understanding of depression neurobiology and possibilities of developing novel rapid antidepressant drugs.

“It is very important to highlight that this is an experimental investigation developed in animals and we cannot guarantee that the same would happen in humans,” Joca told us. “Although one of the drugs we tested is actually used to treat some conditions in humans (ex. cancer and neurological disorders), we cannot assume that these treatments would actually be feasible in humans due to the chance of important side effects associated with the unspecific regulation of gene expression. Nevertheless, the results are very important in pointing to new mechanisms to be further explored to achieve rapid antidepressant effects and/or understand depression neurobiology.”