Depression Treatment: KNT-127 Shows Promise as a Delta Opioid Receptor Agonist
Depression due to psychological stress affects millions of people worldwide. However, most of the existing anti-depressant drugs are slow, prone to development of resistance, and have severe side effects, demanding the need for more effective treatment options.
The Potential of DOP Agonists
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 anti-depressant activity, quick action, and minimal side effects. However, the underlying mechanism of action is not well understood.
To assess the therapeutic and preventive effects of KNT-127 in a mouse model with depression, Prof. Akiyoshi Saitoh, Mr. Toshinori Yoshioka, Jr. Associate Prof. Daisuke Yamada, Prof. Eri Segi-Nishida, and Prof.Hiroshi Nagase conducted a study at the Tokyo University of Science and the University of Tsukuba. The findings of this study were made available online on 30 March, 2023, and published in the journal Neuropharmacology on 4 April, 2023.
Mechanism of Action
The hypothalamic-pituitary-adrenal axis, hippocampal neurogenesis, and neuroinflammation are regarded as the major factors in the processes leading to the development of depression. The researchers aimed to understand the effect of KNT-127 on these parameters to decode its underlying working principle.
The researchers created a mouse model of depression called chronic vicarious social defeat stress (cVSDS) mice by subjecting them to extreme psychological stress for 10 minutes per day for 10 days. KNT-127 was administered to the mice during and after the stress period to assess its efficacy.
The prolonged administration of KNT-127 during and after the stress period significantly improved social interaction and reduced levels of serum corticosterone (a stress hormone in mice) in cVSDS mice. Additionally, KNT-127 administration during stress suppressed stress-induced newborn neuronal death in the hippocampus, while administration after stress did not affect newborn neuron survival rate. KNT-127 also suppressed microglial activation and reduced inflammation in the hippocampus under both models of delivery.
In summary, KNT-127 prevents neuronal inflammation and reduces newborn neuronal death during and after the stress period without affecting neuron formation, resulting in anti-stress and anti-depressant-like effects. Further research is required to gain a better understanding of DOP agonists and their mechanisms underlying anti-depressant effects.
Implications for Treatment
The anti-stress effect of KNT-127 may provide additional benefits for patients undergoing depression treatment. This effect is particularly relevant since patients with depression often face stressful environments even during treatment. The successful clinical development of DOP agonists is expected to offer broader treatment options for depression in the future.