A new mechanism involved in depression has been identified by a team of scientists at McGill University and France’s Institut national de la santé et de la recherche médicale (INSERM). More importantly, they also discovered a way to target it with a drug as effective as classical antidepressants.

The results of the study, which investigated the biological and molecular mechanisms at work in neurons during treatment with a classical antidepressant, adds to the understanding of this illness and could open the door to treatments with fewer side effects.

The work, conducted simultaneously in humans and mice, was designed to show how antidepressants act on two neurotransmitters known to influence mood: serotonin and norepinephrine. Bruno Giros, professor in McGill’s Department of Psychiatry, and Eléni Tzavara, Director of Research at INSERM, led the effort.

Signalling Cascades

When serotonin and norepinephrine come in contact with receptors located on the surface of neurons, they trigger a series of molecular signalling cascades inside the cell. Thus, much as in a relay race, various molecules pass on instructions, to be delivered to the nucleus, telling it to activate or inactivate the expression of genes involved in various biological functions.

One of those signalling cascades that has been identified as being involved in mood regulations is the extracellular signal–regulated kinase (ERK) pathway. But targeting this pathway for drug development has remained too difficult due to it’s complexity.

Antidepressants act directly on two multifunctional neurotransmitters, so they are accompanied by a number of adverse effects. In their study, the researchers show that in mice, one can target a single runner in this relay race, Elk-1, a molecule that steps in for the last lap of the race and that appears to be directly involved in depressive disorders.

“What’s interesting and rather new is that we have shown the advantage of targeting signalling modules (a runner) rather than the entire pathway. This surgical approach should enable us to avoid the adverse effects of classical antidepressants."

explained Giros, who is also a researcher at the Douglas Mental Health University Institute (CIUSSS de l’Ouest-de-l’Île-de-Montréal).

Depression Treatment DIfficulties

For roughly a third of patients suffering from major depressive disorder, the path to healing can prove long because physicians have to find, by trial and error, the appropriate drug and dosage to treat them. Worse still, in approximately 33% of patients, none of the existing antidepressants have any effect.

“The drug we’ve tested could also constitute a treatment with fewer failures,” says Giros. “Classic antidepressants take up to three weeks to have an effect and this new approach could give quicker response times."

Giros’s research has also suggested that Elk-1 shows promise as a therapeutic biomarker for determining which patients are more likely to respond to treatments.

In molecular biology, extracellular signal–regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions. In the MAPK/ERK pathway, Ras activates c-Raf, followed by mitogen-activated protein kinase kinase (abbreviated as MKK, MEK, or MAP2K) and then MAPK1/2.

Ras is typically activated by growth hormones through receptor tyrosine kinases and GRB2/SOS, but may also receive other signals. ERKs are known to activate many transcription factors, such as ELK1, and some downstream protein kinases.

Disruption of the ERK pathway is common in cancers, especially Ras, c-Raf and receptors such as HER2.

Kallia Apazoglou, et al. Antidepressive effects of targeting ELK-1 signal transduction Nature Medicine (2018) doi:10.1038/s41591-018-0011-0

Image: RCSB Protein Data Bank. Wellcome Images

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