4‑(Arylethyl)‑pyrrolo[2,3-d] pyrimidine improves post-traumatic stress disorder in mice by inhibiting mGluR5-regulated ERK1/2-SGK1 signaling pathway

doi:10.12122/j.issn.1673-4254.2025.04.12

Abstract

Abstract:

Objective To observe the effect of 4-(arylethynyl)-pyrrolo[2,3-d] pyrimidine (10b) on post-traumatic stress disorder (PTSD)-like behaviors and ERK1/2-SGK1 signaling pathway in mice. Methods C57BL/6 mouse models exposed to single prolonged stress (SPS) were treated with daily gavage of saline, 10b at low, moderate and high doses, or paroxetine for 14 days. The changes in PTSD-like behaviors of SPS mice with different treatments were observed using behavioral tests. Western blotting and immunofluorescence assay were used to detect the protein expression levels of mGluR5, p-ERK, and SGK1 in the hippocampus of the mice. Pathological changes in the liver and kidney tissues of the mice were examined using HE staining. Molecular docking and molecular dynamics analyses were employed to evaluate the binding stability between the compound 10b and mGluR5. Results Compared to the normal control mice, the SPS mice exhibited obvious PTSD-like behaviors with increased hippocampal expressions of mGluR5 and p-ERK proteins and decreased SGK1 protein expression. Compound 10b significantly ameliorated behavioral abnormalities in SPS mice, inhibited mGluR5 expression, and reversed the dysregulation of p-ERK and SGK1. No obvious liver or kidney toxicity was observed after 10b treatment. Molecular docking and dynamics studies demonstrated a stable interaction between 10b and mGluR5. Conclusion The compound 10b ameliorates PTSD-like behaviors induced by SPS in mice possibly by inhibiting mGluR5 expression to modulate the ERK1/2-SGK1 signaling pathway.

Key words: 4?(arylethynyl)-pyrrolo[2,3-d] pyrimidine, post-traumatic stress disorder, metabotropic glutamate receptors 5, single prolonged stress, ERK1/2, SGK1

Cunbao HE, Shaojie YANG, Guoqi ZHU. 4‑(Arylethyl)‑pyrrolo[2,3-d] pyrimidine improves post-traumatic stress disorder in mice by inhibiting mGluR5-regulated ERK1/2-SGK1 signaling pathway[J]. Journal of Southern Medical University, 2025, 45(4): 765-773.

Figures/Tables 6

Fig.1 Compound 10b structure (A) and experimental protocol (B).

Fig.2 Compound 10b improves anxiety-like behaviors in mice with single prolonged stress (SPS). A-E: Statistics of time in central area, distance in central area, center entries, total distance and mean speed in open field test; F: Percentage of time in open arms in elevated plus maze test; G: Motion trajectory of open field test; *P<0.05 vs Control; #P<0.05 vs SPS.

Fig.3 Compound 10b improves abnormal fear memory in SPS mice. A : Freezing time in the re-exposure phase (○P<0.05: SPS+10b-L vs SPS; ▼P<0.05: SPS+10b-M vs SPS; ▲P<0.05: SPS+10b-H vs SPS; □P<0.05: SPS+PRX vs SPS). B: Freezing time in the extinction phase (*P<0.05 vs Control; #P<0.05 vs SPS).

Fig.4 Effects of compound 10b on expression levels of mGluR5, p-ERK and SGK1 proteins in mouse hippocampus. A: Western blotting and quantitative analysis of mGluR5 expression level. B: Western blotting and quantitative analysis of p-ERK expression levels. C: Western blotting and quantitative analysis of SGK1 expression; D, E: Immunofluorescence staining and fluorescence intensity of mGluR5 in hippocampal CA1 region. *P<0.05 vs Control; #P<0.05 vs SPS.

Fig.5 Effects of compound 10b on liver and kidney histopathology in SPS mice.

Fig.6 Molecular docking and molecular dynamics studies of compound 10b with mGluR5. A: Visualization of the molecular docking of compound 10b with mGluR5. B-D: RMSD, RMSF and energy analysis of molecular dynamics of compound 10b with mGluR5.

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