Stress depression affects millions of people worldwide. However, most current antidepressant medications are slow, prone to developing resistance, and have severe side effects, necessitating the need for more effective treatment options.
Delta opioid receptors (DOPs) are known to play a major role in the development of depression and similar illnesses. Previous studies revealed that DOP agonists (substances that bind DOPs instead of the regular compound and cause the same effect) have improved efficacy and fewer side effects than most current antidepressant medications. Recent studies have identified KNT-127 as a potent DOP agonist with significant antidepressant activity, rapid action, and few side effects. However, the underlying mechanism of action is not well understood.
To this end, Professor Akiyoshi Saitoh, Mr. Toshinori Yoshioka Jr., Associate Professor Daisuke Yamada, and Professor Eri Seiji Nishida, at the University of Tokyo of Science, along with Professor Hiroshi Nagase of the University of Tsukuba, set in order to evaluate the therapeutic and preventive effects of KNT-127 in Depressed mouse model. The results of this study were published online on March 30, 2023, and published in the journal Neuropharmacology on April 4, 2023.
Explaining the motivation behind their study, Professor Saitoh states, “We previously discovered that delta-opioid receptor (DOP) agonists may act quickly and have a low risk of side effects compared to existing drugs. Thus, we worked on them as a novel treatment strategy for depression. In this study, we attempted to elucidate the mechanism of the effects.” Antidepressant-like expression of KNT-127, a selective DOP agonist, in a rat model of depression”.
The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation are key factors in the processes leading to depression. Thus, understanding the effect of KNT-127 on the aforementioned parameters was crucial to deciphering its basic working principle.
To this end, Professor Saito and his team created a mouse model of depression called chronic social defeat stress (cVSDS) rats, by exposing five-week-old male rats to intense psychological stress for 10 minutes a day, repeated for 10 days. Then, 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 a period (anti-stress effect) and after stress (antidepressant effect), significantly improved social interaction and serum corticosterone levels (a hormone secreted under stress in mice) in cVSDS mice. Moreover, administration of KNT-127 during stress suppressed stress-induced neonatal neuronal death in the hippocampus, rather than increasing neurogenesis, or the formation of new neurons. In contrast, when given after stress, KNT-127 did not affect the survival rate of neonatal neurons at all. Moreover, 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, in both models of birth, KNT-127 suppressed microglia activation and thus reduced inflammation in the hippocampus.
In summary, during and after the stress period, KNT-127 prevents neuronal inflammation and reduces neonatal neuronal death without affecting neurogenesis to exert stress-like and antidepressant-like effects, respectively. However, further research is warranted to gain better insights regarding DOP agonists and the mechanism underlying their antidepressant effects.
The anti-stress effect of KNT-127 may provide additional benefits to patients during treatment. “Patients with depression often experience situations where they cannot avoid stressful environments, even during treatment. Therefore, we believe that the additional anti-stress effect during treatment is of important clinical significance,” explains Prof. Saitoh.
Professor Saitoh concludes by sharing their vision for the future, “We expect that the successful clinical development of DOP agonists will greatly expand treatment options for depression in the future.”