Researchers reveal how anti-depressant reduces stress, depression

TOKYO: Millions of individuals worldwide suffer from depression as a result of psychological stress. However, most antidepressant medications are sluggish, prone to resistance, and have severe side effects, necessitating the development of more effective therapy alternatives. Delta opioid receptors (DOPs) have been linked to the development of depression and other mental illnesses.

Previous research has shown that DOP agonists (substances that bind DOPs instead of the ordinary molecule and provide the same effect) have higher efficacy and fewer negative effects than most antidepressant medicines on the market.

KNT-127 has recently been found as a strong DOP agonist with considerable antidepressant effectiveness, rapid action, and few adverse effects. The underlying mechanism of action, however, is not fully known.

To this end, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada, and Prof. Eri Segi-Nishida, at the Tokyo University of Science, along with Prof. Hiroshi Nagase from the University of Tsukuba, set out 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 may quick action and have a low risk of side effects compared to existing drugs. Thus, we have been working on their clinical development as a new treatment strategy for depression.

In this study, we attempted to elucidate the mechanism of 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 regarded as the major factors in the processes leading to the development of depression.

Thus, understanding the effect of KNT-127 on the above parameters was crucial towards decoding its underlying working principle.

To this end, Prof. Saitoh and team created the depression mouse model called chronic vicarious social defeat stress (cVSDS) mice, 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 the mice both during (10 days) and after (28 days later) the stress period, to assess its efficacy.

They observed that prolonged administration of KNT-127 during (anti-stress effect) and after stress (anti-depressant effect) period, significantly improved social interaction and levels of serum corticosterone (a hormone secreted under stress in mice) in cVSDS mice.

Moreover, KNT-127 administration during stress, suppressed stress-induced newborn 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 newborn neuron survival rate 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 hence reduced inflammation in the hippocampus.