Recent studies have discovered that depression is associated with a reduction in a brain process called ‘neurogenesis’- the ability of the brain to produce new brain cells. However, the pathway responsible for this process has, until now, remained unknown.
A new study from King’s College London’s Institute of Psychiatry reveals this formerly unknown molecular pathway leading to depression, suggesting potential new targets for drug discovery. The study, published in Neuropsychopharmacology, shows for the first time that the ‘Hedgehog pathway’ regulates how stress hormones, usually elevated during depression, reduce the number of brain cells.
Depression affects approximately 15 million Americans. The 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 talking treatment, or usually a combination of the two.
In this study, Dr Christoph Anacker from the Centre for the Cellular Basis of Behaviour (CCBB) at King’s Institute of Psychiatry and his team studied human stem cells, which are 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 scientists 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. They discovered that a specific signalling 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 normalise the production of new brain cells.
Dr Christoph Anacker, lead author of the study from King’s Institute of Psychiatry 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 signalling pathway, stress hormones reduce the development of immature ‘stem’ cells into mature ‘brain’ cells.”
Dr. 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 signalling, will allow us to develop much more specific antidepressants in the future.”
Paper reference: Anacker, C. et al. ‘Glucocoticoid-related molecular signalling pathways regulating hippocampal neurogenesis’ Neuropsychopharmacology (2012)
source: [Science Daily]