Treatment of depression faces two main challenges. The first is that almost 50% of patients do not respond well to existing antidepressants.
The second is that conventional medications take a relatively long time – around three to five weeks – to have the desired effect. A group of researchers affiliated with the University of São Paulo (USP) in Brazil set out to tackle the second problem by using epigenetic modulators to try to "erase" the consequences of stress. Epigenetic mechanisms are part of a complex system that controls how and when genes are switched on or off.
Exposure to stress, a key trigger of depression, alters certain epigenetic markers in the brain. Many of these alterations occur in genes associated with neuroplasticity, the brain's ability to change in response to experience. Stress increases DNA methylation in these genes.
DNA methylation is a chromatin remodeling process that regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factors to DNA. Most existing antidepressants are designed to reduce this process.
The team led by Sâmia Joca, a professor at USP and the University of Aarhus in Denmark, decided to conduct an in-depth investigation into the action of BDNF (brain-derived neurotrophic factor), a nervous system protein with well-documented effects on the regulation of neuronal plasticity.
"Stress reduces expression of BDNF and, as shown in the literature, antidepressants have no effect if BDNF signaling is blocked. That's why we focused on BDNF," said Joca, who is affiliated with the Biomolecular Science Department at USP's Ribeirão Preto School of Pharmaceutical Sciences (FCFRP).
The group tested the hypothesis that stress increases methylation of the gene for BDNF, reducing its expression and that this reduction is linked to depressive behavior. "Our starting point was this: if we administered a genetic modulator that inhibited DNA methylation, the process wouldn't happen, BDNF levels would be normal, and there would be an antidepressant effect," Joca…