Neuronal loss has been identified in depression, but its mechanisms are not fully understood. Proteomic analyses provide a novel insight to explore the potential mechanisms of such pathological alterations. In this study, mice were treated with chronic unpredictable mild stress (CUMS) for 2 months to establish depression models. The hippocampus was analyzed for proteomic patterns by mass spectrometry followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Behavioral tests showed that mice receiving CUMS showed depression-like symptoms such as anhedonia in the sucrose preference test (SPT) and behavioral despair in the forced swimming test (FST). CUMS induced anxiety-like behaviors in the open field test (OFT), but did not impair spatial learning and memory ability in the Morris water maze (MWM) test. Out of 4046 quantified proteins, 47 differentially expressed proteins were obtained between the CUMS and control groups. These proteins were functionally enriched in a series of biological processes. Among the notably enriched pathways, necroptosis and ferroptosis were significantly activated. Western blot and biochemical assay analyses identified changes in receptor-interacting protein kinase 3 (RIP3), phosphorylated mixed lineage kinase domain-like protein (p-MLKL), ferritin light chain 1 (Ftl1) and lipid peroxidation that were related to necroptosis and ferroptosis. Further, we found reduced levels of alpha-crystallin B (Cryab) and brain-derived neurotrophic factor (BDNF), which were also associated with neuronal survival. Our study highlighted that necroptosis and ferroptosis were involved in depression and partially account for neuronal loss, thereby providing potentially novel targets for the treatment of depression.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is widely used to treat depression. However, the underlying mechanism has not been identified, and there is uncertainty regarding the optimal choice of stimulus parameters, especially stimulus frequency. Our previous study in mice demonstrated that 10-Hz HF-rTMS ameliorated depression by inducing expression of Homer1a and reducing excitability of cortical pyramidal cells. The aims of this study were to compare the effects of 15-Hz and 25-Hz HF-rTMS in a model of chronic unpredictable mild stress (CUMS)-induced depression and investigate its possible molecular mechanism. Male C57BL/6J mice were treated with CUMS for 28 days followed by 15-Hz and 25-Hz rTMS for 4 weeks. The sucrose preference, open field, forced swimming, and tail suspension tests were used to evaluate depression-like behaviors. Immunostaining was performed to measure neuronal loss and neurogenesis. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Expression of synapse-related proteins and the effects of HF-rTMS on the signaling pathway were examined using Western blot. The results showed that both 15-Hz and 25-Hz rTMS had significant antidepressant effects; 15-Hz rTMS seemed to be more effective than 25-Hz rTMS in preventing neuronal loss and promoting neurogenesis, while 25-Hz rTMS was superior to 15-Hz rTMS in facilitating synaptic plasticity. We also found that 15-Hz and 25-Hz rTMS markedly increased expression of p11, BDNF, Homer1a, and p-trkB proteins. These findings suggest that 15-Hz and 25-Hz HF-rTMS could exert neuroprotective effects to different degrees via multiple perspectives, which at least in part involve the p11/BDNF/Homer1a pathway.

Background Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer’s disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism. Methods SH-SY5Y cells were challenged with Aβ_25-35 and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6 weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal. Results SRS11-92 attenuated Aβ_25-35-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden. Conclusions SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.