ArticleNeurochemical research2024
20-Hydroxyeicosatetraenoic Acid Regulates the Src/EGFR/NF-κB Signaling Pathway Via GPR75 to Activate Microglia and Promote TBI in the Immature Brain.
Article in Neurochemical research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- G protein-coupled receptor 75 mediates depression-like behaviors and HPA axis hyperactivity through an excitatory arcuate-paraventricular nucleus circuit.Acta pharmacologica Sinica · 2026Article
- Targeting mGluR1-Mediated Microglial ER Stress Mitigates Copper-Induced TBI Neuroinflammation.Molecular neurobiology · 2026Article
- GPR75 in glutamatergic neurons regulates body weight.Cell reports · 2026Article
- Gpr75 Deletion in Adipocytes Protects From Diet-Induced Obesity: Changes in Glucose Homeostasis and Inflammatory Responses.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Neuronal GPR75 deficiency protects against diet-induced obesity in a humanized mouse model.Science advances · 2026Article
- TLR4 mediates post-traumatic depression via kynurenine pathway activation in a murine traumatic brain injury model.Frontiers in pharmacology · 2026Article
- Exploring potential targets and molecular mechanisms of traumatic brain injury exacerbated by Benzo(a)pyrene via network toxicology and molecular dynamics simulation.Cell biology and toxicology · 2025Article
- GPR75: Advances, Challenges in Deorphanization, and Potential as a Novel Drug Target for Disease Treatment.International journal of molecular sciences · 2025Review
- Mechanisms mediating effects of cardiotonic steroids in mammalian blood cells.Frontiers in pharmacology · 2025Review
- Blood-activating, depression-relieving formula alleviates post-stroke depression: mechanistic insights from network pharmacology and microglial validation.Frontiers in neurologyArticle
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Authors and funding
13 authors.
Funding
Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE) is associated with secondary damage in traumatic brain injury (TBI) of the immature brain. Microglial activation is pivotal in this process. However, the underlying mechanism of action remains unknown. While 20-HETE interacts with G protein-coupled receptor 75 (GPR75) in some pathological processes, their interaction in brain tissue remains uncertain. This study aimed to investigate whether 20-HETE can activate microglia by binding to GPR75 in TBI of the immature brain. Drug affinity responsive molecular target stability (DARTS) assays, cycloheximide (CHX) chase assays, and auto-dock assays were employed to analyze the interaction between 20-HETE and GPR75. The expression levels of cytochrome P450 4A (CYP4A) and GPR75 in activated microglia in an immature brain TBI model were observed by western blot and multiple immunofluorescence staining. The effects of different levels of 20-HETE expression and lentivirus-mediated GPR75 gene silencing on 20-HETE-induced inflammatory factor release from BV-2 cells were observed by enzyme-linked immunoassay (ELISA). The phosphorylation levels of the downstream Src kinase, epidermal growth factor receptor (EGFR), and nuclear factor (NF)-κB were assessed using western blot. Cell viability and apoptosis were detected by CCK-8 and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. 20-HETE bound to the GPR75 protein and inhibited its degradation. GPR75 gene silencing reversed the 20-HETE-induced inflammatory activation of BV-2 cells, effectively inhibiting the activation of the Src/EGFR/NF-κB pathway and the effects of 20-HETE on cell viability and the apoptosis rate. In contrast, overexpression of GPR75 had the opposite effect. In addition, after immature brain TBI, the 20-HETE and GPR75 expression levels were upregulated in microglia, with significant activation of the Src/EGFR/NF-κB pathway. Inhibition of 20-HETE synthesis with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) produced the opposite effect. 20-HETE regulates the Src/EGFR/NF-κB signaling pathway via GPR75 to activate microglia, promoting immature brain TBI. These findings offer a novel target for promoting the brain injury effect of 20-HETE.
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