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Discovery of Molecular Pathway for Depression Reveals New Drug Targets

Finding may shape future of antidepressant medications (Dec. 6)

Scientists at King’s College London have identified the key molecular pathway leading to depression, revealing potential new targets for drug discovery. The study, published in Neuropsychopharmacology, reveals for the first time that the so-called “Hedgehog pathway” regulates how stress hormones, usually elevated during depression, reduce the number of brain cells.

Recent studies have shown that depression is associated with a reduction in neurogenesis (the ability of the brain to produce new cells). However, the pathway responsible for this process has remained unknown until now.

In the new report, researchers studied human stem cells — the source of new cells in the human brain — to investigate the effect of stress hormones on brain-cell development.

Stress hormones, such as cortisol, are generally elevated in stress and depression. The team studied stem cells in a laboratory and found that high concentrations of cortisol damaged these cells and reduced the number of newborn brain cells. They 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.

Finally, in order 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 to normalize the production of new brain cells.

Dr. Christoph Anacker, lead author of the study, says: “By decreasing the number of new-born 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.”

Anacker continues: “With as much as half of all depressed patients failing to improve with currently available treatments, developing new, more effective antidepressants still remains a great challenge, which makes it crucial to identify new potential mechanisms to target. The discovery of antidepressants has so far been mainly by serendipity. 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.”

Source: King’s College London; December 6, 2012.

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