Antidepressant Agent KNT-127 Reduces Stress as Well as Depression

Depression due to psychological stress affects millions of people worldwide. However, most of the existing antidepressant drugs are slow, prone to development of resistance, and have severe side effects, demanding the need for more effective treatment options.

Delta opioid receptors (DOPs) are known to play a key role in the development of depression and similar diseases. Previous studies have revealed that DOP agonists (substances that bind DOPs instead of the regular compound and cause the same effect) have improved efficacy and lower side effects than most existing anti-depressant drugs. Recent studies have identified KNT-127 as a potent DOP agonist with significant antidepressant activity, quick action, and minimal side effects. However, the underlying mechanism of action is not well understood.

A team of researchers from the University of Tsukuba, set out to assess the therapeutic and preventive effects of KNT-127 in a mouse model with 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 (antidepressant effect) period, significantly improved social interaction and levels of serum corticosterone (a hormone secreted under stress in mice) in cVSDS mice. 

During and post stress period, KNT-127 prevents neuronal inflammation and reduces newborn neuronal death without affecting neuron formation to exert anti-stress and antidepressant-like effects, respectively. 

When talking about added benefits from the anti-stress effect, Prof. Saitoh says: “Patients with depression often have to face situations where they cannot avoid stressful environments, even during treatment. Therefore, we believe that the additional anti-stress effect during the treatment period has important clinical significance.”

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Sources:

Toshinori Yoshioka, Daisuke Yamada, Eri Segi-Nishida, Hiroshi Nagase, Akiyoshi Saitoh. KNT-127, a selective delta opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a chronic vicarious social defeat stress mouse model. Neuropharmacology, 2023; 232: 109511 DOI: 10.1016/j.neuropharm.2023.109511

Tokyo University of Science. “Anti-depressant agent KNT-127 reduces stress as well as depression: Scientists have developed a potential anti-depressant that exhibits anti-stressing as well as anti-depressant effects with minimal side effects.” ScienceDaily. ScienceDaily, 8 May 2023. <www.sciencedaily.com/releases/2023/05/230508104933.htm>.

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