Scientists have developed a potential antidepressant that exhibits anti-stress and antidepressant effects with minimal side effects — ScienceDaily

Delta opioid receptors (DOPs) are known to play a key role in the development of depression and similar diseases. Previous studies have revealed that DOP agonists (substances that bind to DOP instead of the regular compound and cause the same effect) have improved efficacy and fewer side effects than most existing antidepressant medications. Recent studies have identified KNT-127 as a potent DOP agonist with significant antidepressant activity, rapid action, and minimal side effects. However, the underlying mechanism of action is not well understood.

To this end, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr., Associate Prof. Daisuke Yamada and Prof. Eri Segi-Nishida, from Tokyo University of Science, together with Prof. Hiroshi Nagase from the University of Tsukuba, established to evaluate the therapeutic and preventive effects of KNT-127 in a mouse model of depression. The findings of this study became available online on March 30, 2023, and were published in the journal neuropharmacology on April 4, 2023.

Explaining the motivation behind his study, Professor Saitoh explains: “We previously found that delta opioid receptor (DOP) agonists can act quickly and have a low risk of side effects compared to existing drugs. Therefore, we have “We have been working on its clinical application development as a new treatment strategy for depression. In this study, we sought to elucidate the mechanism of the antidepressant-like effects of KNT-127, a selective DOP agonist, in a mouse model of depression.” .

The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis and neuroinflammation are considered the main factors in the processes that lead to the development of depression. Therefore, understanding the effect of KNT-127 on the above parameters was crucial to decoding its underlying working principle.

To this end, Professor Saitoh and his team created the mouse model of depression called chronic vicarious social defeat stress (cVSDS), by exposing five-week-old male mice to extreme psychological stress for 10 minutes per day, repeated for 10 days. Mice were then administered KNT-127 during (10 days) and after (28 days after) the stress period to assess its efficacy.

They observed that prolonged administration of KNT-127 during (anti-stress effect) and after the stress period (antidepressant effect), significantly improved social interaction and serum corticosterone levels (a hormone secreted under stress in mice) in cVSDS mice. Furthermore, administration of KNT-127 during stress suppressed stress-induced neonatal neuronal death in the hippocampus, rather than increasing neurogenesis, or the formation of new neurons. In contrast, when administered after stress, KNT-127 did not affect the survival rate of newborn neurons at all. Furthermore, unlike conventional antidepressants, KNT-127 did not affect neurogenesis even under stress-free conditions.

Psychological stress increases the number of microglia and activated microglia in the brain of cVSDS mice. Interestingly, in both delivery models, KNT-127 suppressed microglial activation and thus reduced inflammation in the hippocampus.

In a nutshell, during and after the stress period, KNT-127 prevents neuronal inflammation and reduces neonatal neuronal death without affecting neuron formation to exert anti-stress and antidepressant effects, respectively. However, further research is warranted to gain a better understanding of DOP agonists and the mechanism underlying their antidepressant effects.

The anti-stress effect of KNT-127 may offer additional benefits to patients during treatment. Prof. Saitoh explains: “Patients with depression often have to deal with situations where they cannot avoid stressful environments, even during treatment. Therefore, we believe that the additional anti-stress effect during the treatment period has significance. important clinical”.

Prof. Saitoh concludes by sharing his vision for the future: “We hope that the successful clinical development of DOP agonists will greatly expand the options for the treatment of depression in the future.”