Depression affects millions of people worldwide as a result of psychological stress. Most antidepressants, on the other hand, are slow-acting, prone to resistance, and have severe side effects, leading to the creation of more effective therapeutic options.
The development of depression and other mental illnesses is associated with the presence of delta opioid receptors (DOP). A previous study showed that DOP agonists (substances that bind DOP instead of the normal molecule and have the same effect) are more effective and have fewer side effects than most antidepressants on the market.
Recently, KNT-127 was discovered to be a potent DOP agonist with significant antidepressant efficacy, rapid onset, and few side effects. However, the underlying mechanism of action is not well understood.
For this purpose Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada and Prof. Eri Segi-Nishida from Tokyo University of Science, along with Prof. Hiroshi Nagase of the University of Tsukuba to evaluate the therapeutic and preventive effects of KNT-127 in a mouse model of depression.
The results of this study were made available online on March 30, 2023 and published in the journal Neuropharmacology on April 4, 2023. Prof. Saitoh explains the motivation behind their study: “We previously found that delta-opioid receptor (DOP) agonists can act quickly and have a low risk of side effects compared to existing drugs.
We are therefore working on their clinical development as a new treatment strategy for depression. In this study, we attempted to elucidate the mechanism of the antidepressant 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 to be the main factors in the processes leading to the development of depression. Understanding the effect of KNT-127 on the above parameters was therefore key to decoding its basic working principle.
For this purpose, Prof. Saitoh and team created a mouse model of depression called chronic vicarious social defeat (cVSDS) mice by exposing five-week-old male mice to extreme psychological stress for 10 minutes a day, repeatedly for 10 days. Next, KNT-127 was administered to mice during (10 days) and after (28 days later) the stress period to evaluate its efficacy.
They observed that prolonged administration of KNT-127 during (anti-stress effect) and after stress (anti-depressant effect) periods significantly improved social interaction and serum corticosterone levels (a stress hormone in mice) in cVSDS mice.
Moreover, administration of KNT-127 during stress suppressed stress-induced death of neonatal neurons 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 non-stress conditions.
Psychological stress increases the number of microglia and activated microglia in the brains of cVSDS mice. Interestingly, in both delivery models, KNT-127 suppressed microglial activation and thereby reduced inflammation in the hippocampus.
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