Worldwide, depression affects 350 million people yet nearly two-thirds of all patients fail to respond to prescribed medications. Meanwhile, relapse is possible and suicide looms. With recent scientific evidence suggesting inflammation plays a central role in the genesis of depression, a new UC Davis study explores an innovative chemical for controlling this often severe psychiatric disorder. The experimental antidepressant acts on the very same enzyme targeted by drugs developed for inflammation-based diseases, say the researchers.
Specifically, the innovative drug works as an inhibitor of soluble epoxide hydrolase or sEH. This enzyme plays a role in several diseases, including hypertension (high blood pressure), pain, cardiac hypertrophy (a thickening of the walls of the heart), and even cancer. According to the authors, postmortem brain samples of patients with psychiatric diseases, including depression and schizophrenia, show a higher expression of sEH than samples from people without disease. Seemingly, an inhibitor of sEH is a worthy target for antidepression.
To explore this possibility, Dr. Bruce Hammock, lead researcher and a distinguished professor in the department of entomology, began with a simple question.
How do you evaluate the effects of a depression drug in animals?
Modeling Depression in Mice
A 2011 protocol study, funded by the National Institute of Mental Health, explores this very same theme. With mood and anxiety disorders affecting one out of every six people during their lifetime, the authors of that study note the development of animal models has been a major challenge to psychiatric researchers. Meanwhile, many scientists believe “the limited availability of animal models may explain the relative paucity of novel [drugs],” wrote Dr. Scott J. Russo of Mount Sinai and his co-authors.
One difficult-to-tackle issue is that patients suffering from depression show a very dynamic range of symptoms, explains Russo and his team. Yet, it is the specific physiological response induced by a particular animal experiment that is useful to the researchers. For example, to bring on symptoms of depression in rodents, scientists have historically used restraint stress, chronic unpredictable stress, and foot-shock stress. Each of these are exactly as they sound from placing a mouse in some form of shackle to constantly changing a mouse’s environment, to repeatedly zapping the rodent’s foot with electricity.
However, only when researchers repeatedly exposed mice to social defeat as the depression-inducing stressor did they see activation of the pituitary-adrenal axis in the mice. This axis, then, became a treatment target as a direct result of this model.
Curious Animal Experiments
The way the “social defeat” model works is researchers use the "resident-intruder" paradigm, where an animal is placed in the cage of other animals of the same species, in a way that inspires a non-lethal conflict. Since mice are territorial, if researchers want to inspire a fight, an easy way to do that is to place a smaller mouse in the cage of older mice who have already made it their home. After being bullied, the smaller mouse will show signs of “social defeat,” even when placed in a new cage with mice of comparable size and age. As discussed in this Psychology Today article, the original mouse will act just like an anxious and fearful human; the hapless rodent will approach the others cautiously, hesitate, turn, and then scamper away.
So, to explore a potent sEH inhibitor known as TPPU, Hammock and his colleagues, who included depression expert Dr. Kenji Hashimoto of Chiba University Center for Forensic Mental Health in Japan, chose social defeat as their experimental protocol.
Following several experiments, including one in which they bred mice without the sEH gene, the team observed that mice lacking the sEH gene did not show depression-like behavior after repeated social-defeat stress. Additionally, expression of sEH protein was higher in key brain regions of chronically stressed mice than in the comparison "control" mice. Pretreatment with TPPU also prevented the onset of depression-like behaviors in the mice after either repeated social-defeat stress or induced inflammation. Finally, TPPU displayed rapid effects in controlling the symptoms of depression induced in the mice.
All these findings suggest not only that sEH plays a key role in depression but also that sEH inhibitors would be appropriate drugs for treating or preventing depression. And, because current antidepressants take weeks to take full effect, the rapid action of this potential drug is noteworthy, the researchers conclude.
Source: Ren Q, Ma M, Ishima T, et al. Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. Proceedings of the National Academy of Sciences. 2016.