4-(芳基乙炔基)-吡咯并[2,3-d]嘧啶通过抑制mGluR5调控ERK1/2-SGK1信号通路改善小鼠创伤后应激障碍  

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

作　　者：何存宝 杨绍杰 朱国旗[1] HE Cunbao;YANG Shaojie;ZHU Guoqi(Key Laboratory of Molecular Biology(Brain Diseases),Anhui University of Chinese Medicine,Hefei 230012,China;Second Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230061,China)

机构地区：[1]安徽中医药大学分子生物学(脑病)重点实验室,安徽合肥230012 [2]安徽中医药大学第二附属医院,安徽合肥230061

出　　处：《南方医科大学学报》2025年第4期765-773,共9页Journal of Southern Medical University

基　　金：国家自然科学基金(82404890);安徽省自然科学基金(2208085MH282);安徽省高等学校科学研究项目(2024AH040137,2024AH051044);新安医学与中医药现代化研究所“揭榜挂帅”项目(2023CXMMTCM013)。

摘　　要：目的评价4-(芳基乙炔基)-吡咯并[2,3-d]嘧啶(10b)对单一长时程应激(SPS)诱导的小鼠创伤后应激障碍(PTSD)样行为及ERK1/2-SGK1信号通路的影响。方法将C57 BL/6小鼠随机分为正常对照组,SPS模型组,化合物10b低、中、高剂量组和帕罗西汀组,6只/组。采用行为学实验评价SPS模型组小鼠的PTSD样行为;Western blotting联合免疫荧光检测小鼠海马组织代谢型谷氨酸受体5(mGluR5)、p-ERK、SGK1蛋白表达水平;HE染色检测肝肾组织的病理损伤;分子对接和分子动力学验证化合物10b与mGluR5结合的稳定性。结果与对照组比较,SPS模型组小鼠表现出PTSD样行为(P<0.05),海马mGluR5和p-ERK蛋白表达升高,SGK1蛋白表达减少(P<0.05),而化合物10b可改善SPS组小鼠的行为异常(P<0.05),并抑制mGluR5表达,逆转p-ERK和SGK1的异常(P<0.05),且无明显肝肾毒性;分子对接和分子动力学结果显示10b与mGluR5结合稳定。结论化合物10b能改善SPS诱导的小鼠PTSD样行为,其机制可能和抑制mGluR5调节ERK1/2-SGK1信号通路相关。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.

关 键 词：4-(芳基乙炔基)-吡咯并[2 3-d]嘧啶 创伤后应激障碍 代谢型谷氨酸受体5 单一长时程应激 ERK1/2 SGK1 

分 类 号：R965[医药卫生—药理学]