KNT-127: A new dual-action antidepressant agent with minimal side effects

Japanese researchers have discovered that KNT-127, a delta opioid receptor agonist, reduces depression parameters in a mouse model with minimal side effects.
Kavita Verma
Antidepressant with both stress-relieving and antidepressant properties
Researchers have created a possible antidepressant that has both stress-relieving and antidepressant properties with little negative side effects.


Millions of people throughout the world suffer from depression, which is a serious global health issue. However, current antidepressant medications have many major drawbacks. Addressing this issue, scientists from the Tokyo University of Science and the University of Tsukuba have developed a new, very effective antidepressant medication that has few side effects and operates rapidly to relieve the symptoms of depression. The new study has been reported in the journal Neuropharmacology.

Delta Opioid Receptors: The key to effective antidepressant therapy?

It is well recognized that Delta Opioid Receptors (DOPs) are crucial for the emergence of depression and related conditions. DOP agonists have thus been identified by researchers as possible antidepressant medications with more efficacy and fewer side effects than most currently available medications. The effectiveness of KNT-127, a selective DOP agonist, was evaluated by the researchers in their study using a mouse model of depression.

KNT-127 exhibits dual nature: Anti-stress and antidepressant

Chronic vicarious social defeat stress (cVSDS) mice, a depression mouse model developed by the researchers, were subjected to high psychological stress for ten days. In order to evaluate KNT-127's effectiveness, it was given both during and after the stressful time. They discovered that long-term administration of KNT-127 before, during, and after stressful times enhanced social behavior and serum levels of the hormone corticosterone, which mice secrete during stress. 

Furthermore, stress-induced newborn neuronal death in the hippocampus was decreased by KNT-127 treatment but neurogenesis was unaffected. When given the following stress, KNT-127 had no impact on the survival rates of neonatal neurons. KNT-127 also inhibited microglial activation, which decreased inflammation in the hippocampus.

The study showed that the powerful DOP agonist KNT-127 exhibits dual nature by functioning as both a stress reliever and an antidepressant, hence expanding the potential of currently available treatments. KNT-127 has anti-stress and antidepressant-like effects during and after stressful periods by preventing neuronal inflammation and lowering neonatal neuronal mortality without influencing neuron development. The discoveries, according to the researchers, will open the door to the creation of brand-new, more advantageous, and side-effect-free remedies for depression.

The anti-stress effect of KNT-127 can offer added benefits for patients at the time of treatment. "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," said Prof. Akiyoshi Saitoh, who was part of this study, in an official release.

"We expect that the successful clinical development of DOP agonists will greatly broaden the options for the treatment of depression in the future," concluded Prof. Saitoh.

Study abstract: 

Delta opioid receptors (DOPs) play an important role in depression and other mood disorders. However, little is known about the underlying physiological mechanisms. The hypothalamic–pituitary–adrenal axis, adult hippocampal neurogenesis, and neuroinflammation are regarded as key pathophysiological factors in depression. In this study, we investigated the influence of DOP activation on those factors in a valid animal model of depression, chronic vicarious social defeat stress (cVSDS) mice. cVSDS mice (male C57BL/6J mice) were produced following a 10-day exposure to witness of social defeat stress, and each evaluation was performed more than 28 days after the stress period. Repeated administrations to cVSDS mice with a selective DOP agonist, KNT-127, both during (10 days) and after (28 days) the stress period respectively improved their decreased social interaction behaviors and increased serum corticosterone levels. When administered during the stress period, KNT-127 suppressed decreases in the hippocampal newborn neuron survival rate in cVSDS mice. Moreover, in both administration paradigms, KNT-127 reduced the number of Iba-1- and CD11b-positive cells in the subgranular zone and the granule cell layer of the hippocampal dentate gyrus, indicating a suppression of cVSDS-induced microglial overactivation. These results suggest that KNT-127 acts over the hypothalamic–pituitary–adrenal axis and regulates neurogenesis and neuroinflammation resulting in anti-stress effects, and the antidepressant-like effects of the DOP agonist are implicated in the suppression of the neuroinflammation. This study presents a new finding on the effects of repeated DOP activations on the pathophysiological states of depression.

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