Antidepressants lower stress, depression, study finds 2023

Stress causes depression in millions worldwide. However, most antidepressants are sluggish, resistant, and have severe side effects, driving the development of better treatments.

DOP agonists (substances that bind DOPs instead of the ordinary molecule) are more effective and have fewer negative effects than most antidepressants.

Recently discovered DOP agonist KNT-127 has substantial antidepressant effectiveness, fast action, and low adverse effects. The mechanism is unclear.

To test KNT-127’s therapeutic and preventive effects in a mouse model of depression, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr., Associate Prof. Daisuke Yamada, Prof. Eri Segi-Nishida, and Prof. Hiroshi Nagase from the University of Tsukuba conducted a study.

DOPs are linked to depression and other mental illnesses.

This work was published online on 30 March 2023 and in Neuropharmacology on 4 April 2023.

“We previously discovered that delta-opioid receptor (DOP) agonists may quick action and have a low risk of side effects compared to existing drugs,” Prof. Saitoh said of their study’s rationale.

Thus, we are developing them as a novel depression therapy. We investigated the mechanism of antidepressant-like effects of KNT-127, a selective DOP agonist, in a mouse model of depression.

Depression is caused by the hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation. Thus, understanding how KNT-127 affected the above parameters was vital to deciphering its operating principle.

Prof. Saitoh and colleagues produced the depression mouse model chronic vicarious social defeat stress (cVSDS) mice by subjecting five-week-old male mice to intense psychological stress for 10 minutes every day for 10 days. To test its effectiveness, KNT-127 was administered to mice during (10 days) and after (28 days) stress.

In cVSDS mice, sustained injection of KNT-127 during and after stress greatly increased social interaction and blood corticosterone levels.

KNT-127 also prevented stress-induced hippocampal neonatal neuronal death. KNT-127 did not influence neonatal neuron survival following stress. KNT-127 did not alter neurogenesis under stress-free settings like conventional antidepressants.

Psychological stress enhances cVSDS mice brain microglia and activation. KNT-127 decreased microglial activation and hippocampal inflammation in both delivery models.