UK researchers say they have identified the key molecular pathway involved in depression – a discovery that one day may lead to better medications.
The study, published in the journal Neuropsychopharmacology, demonstrates how the “Hedgehog pathway” encourages stress hormones and reduces the number of brain cells.
Approximately 10 percent of people suffer from depression, and severity of symptoms can range from feelings of sadness and hopelessness to, in the most severe cases, self-harm or suicide. Treatment for depression involves either medication or cognitive-behavioral therapy treatment, or usually a combination of the two.
Recent studies have demonstrated that depression is associated with a reduction in “neurogenesis,”the ability of the brain to produce new brain cells. But the pathway responsible for this process has, until now, remained unknown.
In this study, Christoph Anacker, Ph.D., lead author of the study from King’s Institute of Psychiatry, and his team studied human stem cells — the source of new cells in the human brain — to investigate the effect of stress hormones on brain cell development.
Researchers have known that stress hormones such as cortisol are generally elevated in stress and depression. In the study, researchers studied stem cells in a laboratory and found that high concentrations of cortisol damaged these stem cells and reduced the number of newborn brain cells.
Investigators also discovered that a specific signaling mechanism in the cell, the Hedgehog pathway, is responsible for this process. Then, using an animal model, the team confirmed that exposure to stress inhibited this pathway in the brain.
As a means to test the findings, the researchers used a compound called purmorphamine, which is known to stimulate the Hedgehog pathway. They found that by using this drug, they were able to reverse the damaging effects of stress hormones, and normalize the production of new brain cells.
The Hedgehog, or Hh, signaling pathway plays an important role in the regulation of cell differentiation and organ formation during normal vertebrate embryonic development; mutations that led to its uncontrolled activity gave rise to fruit fly larvae that had a “spiky” appearance reminiscent of hedgehogs.
Anacker said: “By decreasing the number of newborn cells in the human brain, stress hormones damage many important brain functions and may contribute to the development of depression after a period of chronic stress.
“By inhibiting the Hedgehog signaling pathway, stress hormones reduce the development of immature ‘stem’ cells into mature ‘brain’ cells.”
The finding is significant as nearly half of all depressed patients fail to improve with currently available treatments.
“Developing a drug with a defined effect on the brain, such as increasing the number of new-born brain cells, and with a clear target, such as Hedgehog signaling, will allow us to develop much more specific antidepressants in the future,” said Anacker.
Source: King’s College London