Stress and depression often go hand-in-hand. Now, novel research has shown that a known antidepressant agent, KNT-127, also reduces stress, providing insight into the physiological processes underpinning depression, and has potential for new treatments.
Psychological stress is a major driver of mental illness such as depression, a common condition that affects millions of people worldwide. But the association between psychological stress and depression is unclear.
Previous studies into the link between stress and mental health have used animal models to look at the effect of physical stress on depression, rather than analyzing psychological stress. A new study out of Japan has used a depression mouse model to focus only on animals repeatedly exposed to psychological stress.
For their study, researchers at the Tokyo University of Science tested the effectiveness of KNT-127, a delta opioid agonist, in treating depression in mice.
The opioid system, in addition to playing a central role in pain control, regulates the body’s stress response. Delta opioid receptors (DOPs) in the brain and nervous system have long been known to feature prominently in emotional processing. Genetic studies have shown that knocking out the DOP-encoding gene leads to higher anxiety-related responses and depression-like behaviors.
DOP agonists block the action of delta opioid receptors. Previous studies have demonstrated that KNT-127, a DOP agonist, is an effective antidepressant, producing fewer side effects than existing antidepressant drugs.
“We previously discovered that delta opioid receptor (DOP) agonists may [have a] quick action and have a low risk of side effects compared to existing drugs,” said Akiyoshi Saitoh, corresponding author of the study. “Thus, we have been working on their clinical development as a new treatment strategy for depression.”
The aim of the research was to understand how KNT-127 affected key areas of the brain associated with depression as well as its effect on nerve cells (neurons) and inflammation in the brain (neuroinflammation), which is thought to be associated with depression.
Using their depression mouse model, the researchers exposed five-week-old male mice to extreme psychological stress for 10 minutes a day for 10 days. KNT-127 was given to the mice during the stressful event and for 28 days after the stress period to test its effectiveness. Administering KNT-127 during the stressful event enabled researchers to test the drug's effect on stress while administering it afterwards tested its effect on depression.
The researchers found that KNT-127 given during and after stress significantly improved the mice’s social interaction and lowered levels of the hormone corticosterone, which mice produce in response to stress. They also found that KNT-127 administered during stress slowed neuronal death and reduced neuroinflammation.
The results, the researchers say, provide new insights into the link between DOPs and depression. And they suggest that KNT-127 may be an effective treatment for reducing both stress and depression, which could ultimately benefit depression sufferers.
“Patients with depression often have to face situations where they cannot avoid stressful environments, even during treatment,” Saitoh said. “Therefore, we believe that the additional anti-stress effect during the treatment period has important clinical significance.
Based on their findings, the researchers hope that KNT-127 or other delta opioid agonists will be used to develop new treatments for depression.
“We expect that the successful clinical development of DOP agonists will greatly broaden the options for the treatment of depression in the future,” Saitoh said.
The study was published in the journal Neuropharmacology.
Source: Tokyo University of Science
