summary: Scientists have developed an antidepressant drug that may exert antistress and antidepressant effects with minimal side effects. The drug KNT-127 acts quickly in patients without inducing resistance.
Researchers found that KNT-127 administration during and after extreme psychological stress significantly improved social interactions and reduced hippocampal inflammation.
Important facts:
- KNT-127 is a potent delta opioid receptor (DOP) agonist with pronounced antidepressant and rapid action with minimal side effects.
- Long-term administration of KNT-127 during and after stress significantly improved social interactions, reduced neuronal inflammation, and suppressed stress-induced neonatal neuronal death in the hippocampus in a mouse model of depression. I got
- Administration of KNT-127 did not affect neurogenesis even under stress-free conditions, and the anti-stress effects of KNT-127 may provide additional benefits to patients during treatment.
sauce: Tokyo University of Science
Psychological stress-induced depression affects millions of people worldwide. However, most of the existing antidepressants are slow-acting, prone to tolerance, and have severe side effects, leading to the need for more effective treatment options.
The delta opioid receptor (DOP) is known to play an important role in the development of depression and similar disorders. Previous studies have shown that DOP agonists (substances that bind DOP instead of the regular compound and cause the same effect) have improved efficacy and fewer side effects than most existing antidepressants. I was.
Recent studies have confirmed that KNT-127 is a potent DOP agonist with pronounced antidepressant action, rapid action, and minimal side effects. However, the underlying mechanism of action is poorly understood.
For this purpose, Professor Akiyoshi Saito, Associate Professor Toshinori Yoshioka, Associate Professor Daisuke Yamada, and Professor Eri Segi Nishida of Tokyo University of Science Hiroshi Nagase at the University of Tsukuba set out to evaluate the therapeutic and preventive effects of KNT-127 in a mouse model of depression.
The results of this study were published in a journal neuropharmacology .
Professor Saito explains the motivation for his research as follows. As such, he is working on clinical development as a new treatment strategy for depression.
“In this study, we sought to elucidate the mechanism of antidepressant effects of KNT-127, a selective DOP agonist, in a mouse model of depression.”
The hypothalamic-pituitary-adrenal system, hippocampal neurogenesis, and neuroinflammation are considered key factors in the processes leading to the development of depression. Understanding the effects of her KNT-127 on the above parameters was therefore crucial in deciphering its underlying operating principle.
To this end, Prof. Saito and team exposed 5-week-old male mice to extreme psychological stress for 10 minutes a day, repeated for 10 days, called chronic vicarious social defeat stress (cVSDS) mice. We created a depression mouse model. Next, we administered KNT-127 to mice both during the stress period (after 10 days) and after the stress period (after 28 days) and evaluated its efficacy.
They found that long-term administration (anti-stress effect) and post-stress (anti-depressant effect) of KNT-127 improved social interaction and serum corticosterone (hormone secreted under stress in mice) levels in cVSDS mice. We observed a significant improvement.
Furthermore, KNT-127 administration during stress suppressed stress-induced neonatal neuronal death in the hippocampus rather than increasing neurogenesis or the formation of new neurons.
In contrast, KNT-127 had no effect on neonatal neuronal survival when administered after stress. Moreover, unlike conventional antidepressants, KNT-127 did not affect neurogenesis even in the absence of stress.
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 reduced hippocampal inflammation.
Briefly, during and after stress periods, KNT-127 prevents neuronal inflammation and reduces neonatal neuronal death without affecting neuronal formation, exerting antistress and antidepressant effects, respectively. .
However, further research is needed for 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 on treatment. Professor Saito said, “Depressed patients often face situations in which they cannot avoid stressful environments, even during treatment. I think it makes sense.”
Professor Saito concludes by sharing his vision for the future.
Funding: This work was supported by Cyclic Innovation for Clinical Empowerment as part of the Japan Agency for Medical Research and Development (AMED). [grant number 17pc0101018h0001].
About this psychopharmacological research news
author: Hiroshi Matsuda
sauce: Tokyo University of Science
contact: Hiroshi Matsuda – Tokyo University of Science
image: Image credited to Neuroscience News
Original research: open access.
“KNT-127, a selective delta opioid receptor agonist, exhibits beneficial effects in the hippocampal dentate gyrus in a mouse model of chronic surrogate social defeat stress]Akiyoshi Saito and others neuropharmacology
overview
KNT-127, a selective delta opioid receptor agonist, exhibits beneficial effects in the hippocampal dentate gyrus in a mouse model of chronic surrogate social defeat stress
The delta opioid receptor (DOP) plays an important role in depression and other mood disorders. However, little is known about the underlying physiological mechanisms.
The hypothalamic-pituitary-adrenal system, adult hippocampal neurogenesis, and neuroinflammation are considered important pathophysiological factors in depression.
In this study, we investigated the effects of DOP activation on these factors in chronic vicarious social defeat stress (cVSDS) mice, a valid animal model of depression. A cVSDS mouse (male her C57BL/6J mouse) was generated after 10 days of her exposure to witnesses of social defeat stress, and each assessment was performed ≥28 days after him during the stress period.
Repeated administration of the selective DOP agonist KNT-127 to cVSDS mice during (10 days) and after (28 days) stress decreased social interaction behavior and increased serum corticosterone levels, respectively. Improved. When administered during the stress period, KNT-127 suppressed the decline in hippocampal neonatal neuron survival in his cVSDS mice.
Moreover, in both dosing paradigms, KNT-127 reduced the number of Iba-1- and CD11b-positive cells in the subgranular zone and granule cell layer of the hippocampal dentate gyrus, and inhibited cVSDS-induced microglial hyperactivation. showed.
These results implicate KNT-127 acting on the hypothalamic-pituitary-adrenal axis to modulate neurogenesis and neuroinflammation, resulting in anti-stress effects, and that antidepressant-like effects of DOP agonists are involved in suppressing neuroinflammation. It suggests that
This study presents new findings regarding the effects of repeated DOP activation on the pathophysiological state of depression.
