4-(Arylethyl)-pyrrolo[2,3-d]pyrimidine improves post-traumatic stress disorder in mice by inhibiting mGluR5-regulated ERK1/2-SGK1 signaling pathway
HE Cunbao
YANG Shaojie
ZHU Guoqi
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.
Keywords：4-(arylethynyl)-pyrrolo[23-d]pyrimidinepost-traumatic stress disordermetabotropic glutamate receptors 5single prolonged stressERK1/2SGK1
Publication Date：2025-04-20
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：9( 765-773 )