Protecting new neurons reduces depression caused by stress


April 23, 2014
Brain & Behavior

New class of neuroprotective molecules may lead to improved treatments for depression.

Scientists probing the link between depression and a hormone that controls hunger have found that the hormone’s antidepressant activity is due to its ability to protect newborn neurons in a part of the brain that controls mood, memory, and complex eating behaviors. Moreover, the researchers also showed that a new class of neuroprotective molecules achieves the same effect by working in the same part of the brain, and may thus represent a powerful new approach for treating depression.

“Despite the availability of many antidepressant drugs and other therapeutic approaches, major depression remains very difficult to treat,” says Andrew Pieper, associate professor of psychiatry and neurology at the University of Iowa Carver College of Medicine and Department of Veterans Affairs, and co-senior author of the study.

In the new study, Pieper and colleagues from University of Texas Southwestern Medical Center led by Jeffrey Zigman, associate professor of internal medicine and psychiatry at UT Southwestern, focused on understanding the relationship between depression, the gut hormone ghrelin, and the survival of newborn neurons in the hippocampus, the brain region involved in mood, memory, and eating behaviors.

The hippocampus is one of the few regions in the adult brain where new neurons are continually produced – a process known as neurogenesis. Certain neurological diseases, including depression, interfere with neurogenesis by causing death of these new neurons, leading to a net decrease in the number of new neurons produced in the hippocampus.

Ghrelin, which is produced mainly by the stomach and is best known for its ability to stimulate appetite, also acts as a natural antidepressant. During chronic stress, ghrelin levels rise and limit the severity of depression caused by long-term stress. When mice that are unable to respond to ghrelin experience chronic stress they have more severe depression than normal mice.

In the new study, Pieper and Zigman’s team showed that disrupted neurogenesis is a contributing cause of depression induced by chronic stress, and that ghrelin’s antidepressant effect works through the hormone’s ability to enhance neurogenesis in the hippocampus. Specifically, ghrelin helps block the death of these newborn neurons that otherwise occurs with depression-inducing stress. Importantly, the study also shows that the new “P7C3-class” of neuroprotective compounds, which bolster neurogenesis in the hippocampus, are powerful, fast-acting antidepressants in an animal model of stress-induced depression. The results were published online April 22 in the journal Molecular Psychiatry.

Potential for new antidepressant drugs

The neuroprotective compounds tested in the study were discovered about eight years ago by Pieper, then at UT Southwestern Medical Center, and colleagues there, including Steven McKnight and Joseph Ready. The root compound, known as P7C3, and its analogs protect newborn neurons from cell death, leading to an overall increase in neurogenesis. These compounds have already shown promising neuroprotective effects in models of neurodegenerative disease, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and traumatic brain injury. In the new study, the team investigated whether the neuroprotective P7C3 compounds would reduce depression in mice exposed to chronic stress, by enhancing neurogenesis in the hippocampus.

“Not only did we demonstrate that the P7C3 compounds were able to block the exaggerated stress-induced depression experienced by mice lacking ghrelin receptors, but we also showed that a more active P7C3 analog was able to complement the antidepressant effect of ghrelin in normal mice, increasing the protection against depression caused by chronic stress in these animals,” Zigman explains.

“The P7C3 compounds showed potent antidepressant activity that was based on their neurogenesis-promoting properties,” Pieper adds. “Another exciting finding was that our experiments showed that the highly active P7C3 analog acted more rapidly and was more effective [at enhancing neurogenesis] than a wide range of currently available antidepressant drugs.”

The findings suggest that P7C3-based compounds may represent a new approach for treating depression. Drugs based on P7C3 might be particularly helpful for treating depression associated with chronic stress and depression associated with a reduced response to ghrelin activity, which may occur in conditions such as obesity and anorexia nervosa.

Future studies, including clinical trials, will be needed to investigate whether the findings are applicable to other forms of depression, and determine whether the P7C3 class will have antidepressant effects in people with major depression. The study was funded in part by grants from the National Institutes of Health (1R01MH085298, 1R01DA024680, T32DA007290, DA016765, DA023555, 1RO1MH087986).




Protecting new neurons reduces depression caused by stress

5 Responses to Protecting new neurons reduces depression caused by stress

  1. 14038502 - Karla Watson May 1, 2014 at 4:21 am #

    It is really fascinating to continuously discover the complex processes are bodies are capable of doing in order to help us function in our everyday lives, how a hormone can both affect ones appetite and protect valuable neurons in our brains and essentially fight depression.

    It is inspiring to see that there are scientists searching for new ways to fight depression, a mental illness that so many don’t take seriously. The P7C3 compound seems promising, but I must agree with the previous comments with respect to more tests being done on the effects it will have on humans, when dealing with the brain, nothing should be left to chance.

    Stress is indeed inevitable, like Inge stated earlier, and how we as individuals deal with it is very different, but it is always better to try alternative methods before getting hooked on the idea that drugs can fix all our problems, there are some severe cases where the alternatives are not enough to help the negative effects of depression but even though they cannot solve the problem entirely, maybe they can cushion the blow. Exercise and a healthy diet is always good to have.

  2. Ashleigh van Heerden [14020590] April 30, 2014 at 8:43 am #

    It is very interesting that a hormone Ghrelin- which stimulates appetite- is also used by our bodies to combat the effects of depression on new neurons in the hippocampus. I can’t help but think if the hormone has more than one purpose or if there is actually a link between preventing the death of new neurons in the hippocampus and stimulating the appetite of a person?
    However looking at a woman’s perspective this might cause a vicious cycle if she feels depressed because of her figure. For this reason the hormone Ghrelin would not be that effective since it would stimulate appetite and maybe lead to more weight gain. This would also largely explain why women are more susceptible to depression than men and is also the reason why I think that P7C3 holds so much promise in being a ‘substitute’ for the natural antidepressant Ghrelin.
    But here I also agree with Ursula Ahmad . Although the new compound may help the side-effects and the efficacy of this compound must also be studied to determine whether it can be a suitable ‘substitute’ for Ghrelin and as we all know animal trails do not necessarily predict the outcome of how humans would react to a certain drug.

  3. Inge Hugo (14022070) April 28, 2014 at 2:33 am #

    In todays society stress is inevitable. It is amazing how most people suffer from some state of stress but what is frightening is how many people prefer not looking to natural remedies first for dealing with stress such as exercising, listening to music, taking up a calming hobby(knitting, reading, gardening,surfing) and by making sure they eat right and get good rest. Also by limiting their consumption of alcohol, caffeine, and sugar; and if they smoke, they should quit because why load your body with a number of antidepressants but continue using unhealthy substances that just induces more stress and anxiety. If dealing with stress (which leads to depression) in a healthy, natural way has not worked for you then these new antidepressants could make a great breakthrough for you. But I believe to start at the root of the problem first before you depend on another unpredictable pill. Every persons body is different and will react differently to certain medicine. Your body is designed to handle brief periods of stress from time to time.

    If the P7C3 compounds enhances neurogenesis in the hippocampus just like the ghrelin hormone is suppose to, wont it also increase appetite?
    Up to what stage can the P7C3 compounds improve Amyotrophic lateral sclerosis (ALS) because ALS can progress to some very serious stages where patients cannot swallow anymore. Most people with ALS die of respiratory failure or pneumonia, will the P7C3 compound help before it is too late? And could this new P7C3 compound improve Alzheimer’s disease and dementia?

    Inge Hugo
    14022070

  4. Chloe Declercq- 14072573 April 27, 2014 at 3:29 am #

    The research conducted by Pieper and Zigman’s team could possibly solve the ever increasing problem of depression that is so prevalent in our modern society. Depression should be recognized and treated as any other medical condition, rather than simply ignored. This research not only reveals that depression is a condition that can be linked to chronic stress, but also reveals alternative treatment to depression.

    Pieper states that “active P7C3 analog acted more rapidly and was more effective than” most antidepressants. However, the question arises concerning the profitability and availability of attaining P7C3.

    Submitted: 27/04/2014
    Written by: 14072573

  5. Ursula Ahmad April 27, 2014 at 2:21 am #

    It is interesting to note that science has developed and advanced to such an extent as to understand the complex relationship between depression and the gut hormone Ghrelin, as well as pin point that Ghrelin in fact acts as a natural anti-depressant by protecting newborn neurons in the hippocampus. This process carried out by the human body which regulates depression when stress levels are peaked is indeed remarkable.

    According to the new study shown by Pieper and Zigman’s team, it is concluded that Ghrelin helps to block the death of newborn neurons that otherwise occurs with depression-induced stress. One of the main concerns could be that Ghrelin or a similar form of this hormone is going to be produced by pharmaceutical companies and prescribed to those who suffer from depression. The alarming point about this is that an imbalance of hormones in the body could lead to adverse effects on the body. For instance, if the drug is taken in excess or if it is generally taken incorrectly. One could however, argue that any drug taken incorrectly could lead unpleasant effects.

    More tests and studies should be conducted (as well as more positive and useful statistics should be obtained) on the uses and effects of Ghrelin before it is put into drug form and prescribed to patients.

    Ursula Ahmad – 14114870
    Lecturer: Naomi Boakye
    Submitted on: 4/27/2014

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