Major depressive disorder (MDD) and other mental disorders are frequently brought on by psychological stress. It is yet unknown how stress contributes to MDD, despite it being one of the most prevalent diseases in the world. However, the majority of antidepressant medications currently available are cumbersome, prone to resistance development, and have negative side effects, necessitating the need for more efficient treatment choices. Unfortunately, most animal models of depression are caused by repeatedly exposing the animals to physical stress rather than psychological stress, which makes it difficult to understand the relationship between psychological stress and depressive states.
Depression
KNT-127 promotes microglia formation
Table of Contents
It is well recognized that delta opioid receptors (DOPs) are crucial for the emergence of depression and related conditions. Previous research has shown that compared to the majority of currently available anti-depressant medications, DOP agonists (substances that bind DOPs instead of the ordinary molecule and generate the same effect) have increased efficacy and fewer negative effects. According to recent studies, KNT-127 is a powerful DOP agonist with strong antidepressant effectiveness, fast onset, and few adverse effects. However, it is unclear what causes the underlying mechanism of action.
In order to investigate these effects, a team of researchers from the University of Tsukuba decided to study the therapeutic and preventive effects of KNT-127 in a mouse model with depression. The main contributors to the development of depression are thought to include neuroinflammation, hippocampal neurogenesis, and the hypothalamic-pituitary-adrenal axis. Deciphering KNT-127’s basic working principle, therefore, required a thorough understanding of how it affected the aforementioned variables. Chronic vicarious social defeat stress (cVSDS) mice were developed by the scientists by subjecting five-week-old male mice to intense psychological stress for 10 minutes each day for ten consecutive days. The effectiveness of KNT-127 was then evaluated by giving it to the mice both during (10 days) and after (28 days later) the stressful time.
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They discovered that long-term administration of KNT-127 significantly increased social interaction and serum corticosterone levels in cVSDS mice throughout the stress phase (anti-stress effect) and after (antidepressant impact). Furthermore, in the brains of cVSDS mice, psychological stress increased the amount of microglia and activated microglia. It’s interesting to note that KNT-127 decreased microglial activation in both delivery methods, reducing inflammation in the hippocampus. In a nutshell, KNT-127 has anti-stress and antidepressant-like actions during and after stressful periods by preventing neuronal inflammation and lowering neonatal neuronal mortality without influencing neuron development.
Clinical significance
Additional advantages for patients with MDD during treatment could result from the anti-stress effect of KNT-127. Even when receiving treatment, depressed patients frequently encounter circumstances where they are unable to avoid unpleasant environments. The added anti-stress effect during the therapy period could have significant clinical value.
Conclusion
In this work, a novel finding regarding the impact of recurrent DOP activations on the pathophysiological stages of depression is presented. Future possibilities for treating depression should become significantly more varied as a result of the successful clinical development of DOP agonists.
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