Managing both stress and depression – a new potential depression treatment with minimal side effects

New research has demonstrated the antidepressant and antistress effects of KNT-127, a potent delta opioid receptor (DOP) agonist, in a mouse model. The study found that KNT-127 reduced inflammation and neonatal neuronal death in the hippocampus, potentially offering a more effective, faster-acting treatment for depression with fewer side effects than conventional antidepressants.

Researchers have developed a potential depression treatment that demonstrates both stress-relieving and antidepressant effects with minimal side effects.

Millions of individuals globally struggle with depression stemming from psychological stress. However, the majority of existing antidepressant medications suffer from limitations, such as slow onset of action, the potential for the development of resistance, and serious side effects, necessitating the need for more effective treatment options.

Delta opioid receptors (DOPs) have been identified as contributing to the development of depression and related disorders. Previous research has shown that DOP agonists (agents that bind to DOPs, mimicking the action of the naturally occurring substance) exhibit improved efficacy and fewer side effects compared to most conventional antidepressants. Recent studies have focused on KNT-127, a potent DOP agonist, which shows significant antidepressant effect, rapid onset of action and minimal side effects. Yet the precise mechanism of its function is still not well understood.

For this purpose, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada, and Prof. Eri Segi-Nishida, at Tokyo University of Science together 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 of depression. The results of this study were recently published in the journal Neuropharmacology.

Prof. Saitoh explains the motivation behind their study, “We have previously discovered that delta-opioid receptor (DOP) agonists can act quickly 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 sought to elucidate the mechanism of antidepressant-like effects of KNT-127, a selective DOP agonist, in a mouse model of depression.”

Researchers from Japan demonstrate that a DOP agonist, KNT-127, alters the hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation to exhibit therapeutic and prophylactic effects. Credit: 202102 Frontal plane of the brain hippocampus” by DataBase Center for Life Science (DBCLS)

The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis and neuroinflammation are considered the most important factors in the processes leading to the development of depression. Thus, understanding the effect of KNT-127 on the above parameters was crucial to decipher its underlying working principle.

For this purpose, Prof. Saitoh and team depression mouse model called cVSDS mice (chronic vicarious social defeat stress) by subjecting five-week-old male mice to extreme psychological stress for 10 minutes a 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 effectiveness.

They observed that prolonged administration of KNT-127 during (anti-stress effect) and after stress (anti-depressive effect) period, significantly improved social interaction and levels of serum corticosterone (a hormone secreted during stress in mice) in cVSDS mice. Furthermore, KNT-127 administration during stress suppressed stress-induced neonatal neuronal death in the hippocampus rather than increasing neurogenesis or the formation of new neurons. In contrast, KNT-127 did not affect the survival rate of newborn neurons at all when administered after stress. 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 brain of cVSDS mice. Interestingly, under both delivery models, KNT-127 suppressed microglial activation and thus reduced inflammation in the hippocampus.

In a nutshell, during and after the stress period, KNT-127 prevents neuronal inflammation and reduces neonatal neuronal death without affecting neuron formation to exert anti-stress and anti-depressant-like effects, respectively. However, further research is warranted for better insight regarding DOP agonists and the mechanism underlying their anti-depressant effects.

The antistress effect of KNT-127 may provide additional benefits to patients during treatment. Prof. Saitoh elaborates: “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.”

Prof. Saitoh concludes by sharing their vision for the future: “We expect that the successful clinical development of DOP agonists will greatly expand the possibilities for the treatment of depression in the future.”

Reference: “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” by Toshinori Yoshioka, Daisuke Yamada, Eri Segi-Nishida, Hiroshi Nagase and Akiyoshi, March 30 2023, Neuropharmacology.
DOI: 10.1016/j.neuropharm.2023.109511

This work was supported by Cyclic Innovation for Clinical Empowerment as part of the Japan Agency for Medical Research and Development (AMED).