Millions of people around the world suffer from depression as a result of psychological stress. However, most antidepressant drugs are sluggish, prone to resistance, and have severe side effects, necessitating the development of more effective therapy alternatives. Delta opioid receptors (DOP) have been linked to the development of depression and other psychiatric illnesses. Previous research has shown that DOP agonists (substances that bind to DOP instead of the normal molecule and provide similar effects) have higher efficacy and fewer negative effects than most antidepressant drugs on the market.
KNT-127 has recently been found to be a strong DOP agonist with considerable antidepressant effectiveness, rapid action, and few adverse effects. However, the underlying mechanism of action is not fully known. For this, Prof. of Tokyo University of Science. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada, and Prof. Eri Seigi-Nishida, along with Prof. of the University of Tsukuba. Set by Hiroshi Nagase. To assess the therapeutic and preventive effects of KNT-127 in a mouse model with depression. The findings of this study were made available online on 30 March 2023 and published in the journal Neuropharmacology on 4 April 2023.
Explaining the motivation behind their study, Prof Saitoh explains, “We previously discovered that delta-opioid receptor (DOP) agonists can be quick-acting and have a lower risk of side effects than existing drugs. Thus, we are working on their clinical development as a new treatment strategy for depression. In this study, we demonstrated the antidepressant-like effects of KNT-127, a selective DOP agonist, in a mouse model of depression. Tried to explain the mechanism.
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The hypothalamic–pituitary–adrenal axis, hippocampal neurogenesis, and neuroinflammation are thought to be key factors in the processes leading to the development of depression. Thus, understanding the effect of KNT-127 on the above parameters was crucial to decode its underlying working principle.
For this, Prof. Saitoh and team created a depression mouse model called chronic vicarious social defeat stress (cVSDS) rats by exposing five-week-old male mice to extreme psychological stress for 10 minutes per day, repeated for 10 days. Next, KNT-127 was given to mice during (10 days later) and after (28 days later) the stress period, to assess its efficacy.
They observed that after long-term administration of KNT-127 (anti-stress effect) and a period of stress (anti-depressant effect), social interaction and serum corticosterone (a hormone secreted under stress in rats) levels in cVSDS rats There has been a lot of improvement.
Furthermore, KNT-127 administration during stress suppressed stress-induced neonatal neuronal death in the hippocampus, instead of increasing neurogenesis or the formation of new neurons. In contrast, when administered after stress, KNT-127 did not affect newborn neuron survival rates 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 brains of cVSDS mice. Interestingly, under both models of delivery, KNT-127 suppressed microglial activation and therefore reduced inflammation in the hippocampus.