Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway

• Published in: Journal of neuroinflammation Vol. 19; no. 1; p. 117
• Main Authors: Lan, Tian, Wu, Yuhan, Zhang, Yulei, Li, Shuhan, Zhu, Zhanpeng, Wang, Liyan, Mao, Xueqin, Li, Ye, Fan, Cuiqin, Wang, Wenjing, Yu, Shu Yan
• Format: Journal Article
• Language: English
• Published: England BioMed Central 24-05-2022; BMC
• Subjects: 5-HT2C receptor; Acetamides - pharmacology; Agomelatine; Animals; Antibodies; Antidepressive Agents - pharmacology; Anxiety; Apoptosis; Autophagy; Behavior; Cytokines; Dentate gyrus; Depression; Depression - chemically induced; Depression - drug therapy; Depression - pathology; Drinking water; Electron microscopy; Experiments; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; Gαi-2; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Immunoblotting; Immunofluorescence; Immunoprecipitation; Inflammation; International organizations; Lipopolysaccharides; Lipopolysaccharides - pharmacology; MAP kinase; MAP Kinase Kinase Kinase 5 - metabolism; Mental depression; Molecular modelling; Naphthalenes - pharmacology; Neurogenesis; Neurons - drug effects; Neurons - pathology; Neuroprotection; Protein kinase A; Rats; Receptor, Serotonin, 5-HT2C - metabolism; Serotonin S2 receptors; Signal Transduction; Sucrose; Depression; 5-HT2C receptor; Agomelatine; Gαi-2; Apoptosis
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02479-x

Agomelatine has been shown to be effective in the treatment of depression, but the molecular mechanisms underlying its antidepressant effects have yet to be elucidated. Identification of these molecular mechanisms would not only offer new insights into the basis for depression but also provide the foundation for the development of novel treatments for this disorder.
Intraperitoneal injection of LPS was used to induce depression-like behaviors in rats. The interactions of the 5-HT2C reporter and Gαi-2 were verified by immunoprecipitation or immunofluorescence assay. Inflammatory related proteins, autophagy related proteins and apoptosis markers were verified by immunoblotting or immunofluorescence assay. Finally, electron microscopy analysis was used to observe the synapse and ultrastructural pathology.
Here, we found that the capacity for agomelatine to ameliorate depression and anxiety in a lipopolysaccharide (LPS)-induced rat model of depression was associated with an alleviation of neuroinflammation, abnormal autophagy and neuronal apoptosis as well as the promotion of neurogenesis in the hippocampal dentate gyrus (DG) region of these rats. We also found that the 5-HT2C receptor is coupled with G alphai (2) (Gαi-2) protein within hippocampal neurons and, agomelatine, acting as a 5-HT2C receptor antagonist, can up-regulate activity of the Gαi-2-cAMP-PKA pathway. Such events then suppress activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway, a member of the mitogen-activated protein kinase (MAPK) family involved in pathological processes of many diseases.
Taken together, these results suggest that agomelatine plays a neuroprotective role in regulating neuroinflammation, autophagy disorder and apoptosis in this LPS-induced rat model of depression, effects which are associated with the display of antidepressant behaviors. These findings provide evidence for some of the potential mechanisms for the antidepressant effects of agomelatine.