[Retracted] Agomelatine Softens Depressive‐Like Behavior through the Regulation of Autophagy and Apoptosis

Abstract

Depression is a common and disabling mental disorder with high recurrence rate. Searching for more effective treatments for depression is a long-standing primary objective in neuroscience. Agomelatine (AGO) was reported as an antidepressant with unique pharmacological effects. However, its effects and the underlying mechanism are still unclear. In this study, we sought to evaluate the antidepressant effects of AGO on the chronic restraint stress (CRS) mouse model and preliminarily investigate its effects on the gut microbial metabolites. The CRS model mice were established in 28 days with AGO (60 mg/kg/day, by oral) or fluoxetine (15 mg/kg/day, by oral) administration. The number of behavioral tests was conducted to evaluate the effect of AGO on depression-like behavior alleviation. Meanwhile, the expression of the BDNF/TrkB/pERK signaling pathway, apoptosis, autophagy, and inflammatory protein markers were assessed using western blot and immunofluorescence. Our findings show that AGO can attenuate the depressive-like behavior that significantly appeared in both sucrose preference and forced swimming tests. Additionally, a noticeable upregulation of autophagy including Beclin1 and LC3II, microglial activity marker Iba-1, and BDNF/TrkB/pERK signaling pathways are indicated. An obvious decreased expression of NF-κB, iNOS, and nNOS as well as apoptosis including Bax is observed in AGO administration mice. On the other hand, we found that AGO impacted the rebalancing of short-chain fatty acids (SCFAs) in mouse feces. Altogether, these findings suggest that AGO can exert antidepressant effects in a different molecular mechanism.

Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression

“…This antiapoptotic gene was induced only by the drug, both in the basal condition as well as after stress exposure. Bcl-xL is known to have a pronounced neurotrophic effect supporting neuronal survival [ 45 ], and its modulation by the pharmacological treatment is in agreement with the reported antiapoptotic properties of agomelatine itself [ 46 , 47 ] and of other antidepressants [ 48 , 49 , 50 ]. Thus, in addition to the anti-inflammatory properties, agomelatine also possesses a neuroprotective role that might act together to normalize the stress-induced activation of the IL-6 pathway and its deleterious effects.…”

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

“…Recently, cumulative HPA axis activities have been assessed based on hair cortisol levels, and the results suggest that stress and depressive symptoms are related to high cortisol levels [17,18]. Furthermore, in stress-induced depression model animals, the blood corticosterone concentration increased, and the brain BDNF level decreased, with resulting inflammation in the hippocampus and prefrontal cortex [19][20][21], while chronic administration of corticosterone to rodents induced a similar pathogenesis [22,23]. These results suggest that HPA axis-mediated dysregulation of stress response (i.e., HPA axis hyper-activation) contributes to the development and progress of depressive symptoms.…”

miR-124 Exacerbates depressive-like behavior by targeting Ezh2 to induce autophagy

“…Therefore, autophagy is considered to be an important part of the stress response (Kumsta et al, 2017). A growing number of clinical studies and animal models of depression have shown that the abnormal expressions of ATG genes and proteins are involved in the pathophysiology of MDD and the mechanism of antidepressants, including LC3, P62, and Atg7 (Shu et al, 2019;Zhang et al, 2020;Chen et al, 2021;Scaini et al, 2021;Sakai et al, 2022). Moreover, in our previous study, we constructed a diagnostic model using ATGs and found that a model of four ATGs (PDK4, NRG1, EphB2, and GPR18) had a good capacity to distinguish MDD patients from controls (He et al, 2021).…”

“…Ezh2 is a histone-lysine N-methyltransferase enzyme (Borbone et al ., 2011), which played an important role in the epigenetic silencing of target genes (Huqun et al ., 2012). Some studies have found that Ezh2 participated in the process of autophagy by regulating ATG proteins, such as LC3, Atg7, Beclin1, P62, and Stat3 (Li et al ., 2018; Ma et al ., 2018; Chen et al ., 2019, 2020). To our knowledge, only one study has explored the association between Ezh2 and depression, which found that Ezh2 was involved in the susceptibility to depression-like behaviors and neuroinflammation in the hippocampus and prefrontal cortex in different aged mice (Wang et al ., 2020).…”