AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models

Abstract

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.

Integrating network pharmacology with molecular docking to rationalize the ethnomedicinal use of Alchornea laxiflora (Benth.) Pax & K. Hoffm. for efficient treatment of depression

“…A plethora of evidence suggests that PI3K-AKT signaling is a crucial pathway involved in the pathogenesis of depression ( Li et al, 2023 ). PI3K-Akt signaling regulates various neuronal activities such as synaptic neuroplasticity, cell proliferation, cell migration, and apoptosis ( Matsuda et al, 2019 ).…”

“…Frontiers in Pharmacology frontiersin.org pathway, suggesting their critical role in the pathogenesis of depression. Among these pathways, the literature review showed a significant association between the PI3K-Akt signaling pathway (hsa04151) and MAPK signaling pathway (hsa04010) in the depression pathophysiology, suggesting targeting of these pathways by A. laxiflora's bioactive compounds as a possible mechanism of action (Su et al, 2017;Li et al, 2023). Notably, most of the PPI network's hub genes were involved in the PI3K-Akt signaling pathway (hsa04151), highlighting the importance of this pathway for identifying the underlying mechanism of A. laxiflora in depression in future exploratory studies.…”

tiRNA‐Gly‐GCC‐001 in major depressive disorder: Promising diagnostic and therapeutic biomarker

“…Furthermore, the MAPK and Ras signalling pathways were involved the target tiRNA-Gly-GCC-001 genes in KEGG analysis. Interestingly, the MAPK and Ras signalling pathways are modulated by stress and have been previously implicated in MDD and treatment response in human and animal models (Li, Teng, et al, 2023;Lopez et al, 2017) BDNF levels correlating with depression severity and recurrence (Greenberg et al, 2009;Park & Poo, 2013). BDNF also influences cell differentiation, migration and proliferation of cells (Monteiro et al, 2017).…”

Pharmacological investigation of taxifolin for its therapeutic potential in depression

“…Depression typically has a chronic course and significantly impairs individuals' capacity to work and their overall quality of life [ 1 ]. According to the World Health Organization (WHO), depression is anticipated to be the second most common cause of disease and disability by 2030, making it a major public health concern [ 2 ]. Over 300 million individuals worldwide suffer from depression, it is considered as one of the most frequent, costly and debilitating mental disorders [ 3 ].…”