A new study demonstrated antidepressant and antistress effects of KNT-127, a potent delta opioid receptor (DOP) agonist, in a mouse model. This study shows that KNT-127 reduces hippocampal inflammation and neonatal neuronal death, potentially providing a more effective and fast-acting treatment for depression with fewer side effects than conventional antidepressants. showed that it has potential.
Researchers have developed a potential depression treatment that demonstrates both stress-reducing and antidepressant benefits with minimal side effects.
Millions of people worldwide suffer from depression caused by psychological stress. However, most of the existing antidepressants have limitations such as slow action, potential for resistance development, and severe side effects, and there is a need for more effective treatment options.
The delta opioid receptor (DOP) has been identified as involved in the progression of depression and related disorders. Previous studies have shown that DOP agonists (agents that bind to DOP and mimic the actions of natural substances) have improved efficacy and fewer side effects compared to most conventional antidepressants. . Recent studies have focused on KNT-127, a potent DOP agonist, demonstrating significant antidepressant efficacy, rapid onset of action, and minimal side effects. However, the exact mechanism of its operation is still poorly understood.
To this end, Professors Akiyoshi Saito, Toshinori Yoshioka, Associate Professor Daisuke Yamada, Professor Eri Seginishida of Tokyo University of Science and Professor Hiroshi Nagase of University of Tsukuba investigated the treatment of KNT-127 in a mouse model of depression. A study was conducted to evaluate efficacy and preventive efficacy.The results of this study were recently published in a journal neuropharmacology.
Professor Saito explains the motivation behind the research: “We have previously found that delta opioid receptor (DOP) agonists may have a faster effect and a lower risk of side effects compared to existing drugs. We are committed to clinical development as a strategy.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.”
Japanese researchers have demonstrated that the DOP agonist KNT-127 alters the hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation, showing therapeutic and preventive effects. Credit: 202102 “Frontal aspect of brain hippocampus” Life Science Database Center (DBCLS)
The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation are thought to be key factors in the pathogenesis of depression. Understanding the effects of her KNT-127 on the above parameters was therefore important for deciphering its underlying operating principle.
To this end, Prof. Saito and his team exposed 5-week-old male mice to extreme psychological stress for 10 minutes a day for 10 days repeatedly to induce chronic alternative social defeat stress (cVSDS) mice. We created a mouse model of depression called We then administered KNT-127 to mice both during the stress period (10 days) and after the stress period (28 days later) and evaluated its efficacy.
They found that long-term administration of KNT-127 during (anti-stress effect) and after (anti-depressant effect) the stress period resulted in social interactions in cVSDS mice and serum corticosterone (secreted under stress in mice). We observed significant improvements in hormone levels. Moreover, KNT-127 administration during stress suppressed neonatal neuronal death in the hippocampus induced by stress rather than increasing neurogenesis or formation of new neurons. In contrast, post-stress administration of KNT-127 had no effect on survival of neonatal neurons. Moreover, unlike conventional antidepressants, KNT-127 did not affect neurogenesis even under non-stressful 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, thereby reducing hippocampal inflammation.
In short, KNT-127 prevents neuronal inflammation and reduces neonatal neuronal death during and after stress, without affecting neurogenesis, with antistress and antidepressant-like effects, respectively. will demonstrate. However, further studies are needed to gain better insight into the mechanisms underlying DOP agonists and their antidepressant effects.
The anti-stress effects of KNT-127 may provide additional benefits to patients undergoing treatment. Professor Saito elaborates as follows. “People with depression often face situations in which they cannot avoid stressful environments even during treatment. I have.”
Professor Saito concluded his vision for the future by saying, “I hope that the successful clinical development of DOP agonists will greatly expand options for treating depression in the future.”
Reference: “KNT-127, a selective delta opioid receptor agonist, exhibits beneficial effects in the hippocampal dentate gyrus in a mouse model of chronic compensatory social defeat stress” Toshinori Yoshioka, Daisuke Yamada, Eri Seginishida, Hiroshi Nagase , Akiyoshi Saito, March 30, 2023 neuropharmacology.
DOI: 10.1016/j.neuropharm.2023.109511
This research was supported by Cyclic Innovation for Clinical Empowerment as part of the Japan Agency for Medical Research and Development (AMED).
