中国病理生理杂志2026，Vol.42Issue(1)：1-12,12.DOI:10.3969/j.issn.1000-4718.2026.01.001
MRTF-A通过激活自噬减轻大鼠脑缺血再灌注后突触损伤的机制探寻与新药筛选
Exploration of mechanism underlying MRTF-A-mediated autophagy ac-tivation in attenuating synaptic damage after cerebral ischemia-reperfu-sion in rats and screening of novel therapeutic agents
摘要
Abstract
AIM:Cerebral ischemia-reperfusion(I/R)injury remains a major clinical challenge with limited therapeutic options.Myocardin-related transcription factor-A(MRTF-A)has emerged as a regulator of cellular stress re-sponses,but its role in neuroprotection and potential as a pharmacological target in stroke is not fully understood.This study aims to elucidate the molecular mechanism by which MRTF-A confers neuroprotection in cerebral I/R injury and to identify MRTF-A-targeted compounds with therapeutic potential.METHODS:A rat model of transient middle cerebral artery occlusion(MCAO)was used to simulate cerebral I/R injury.Rats were randomized into six groups:sham,MCAO,MRTF-A overexpression,MRTF-A knockdown,autophagy inhibition(3-methyladenine),and autophagy activation(rapa-mycin).MRTF-A levels were modulated via lentiviral delivery.Autophagy and synaptic plasticity proteins were studied by Western blot and immunofluorescence assessed protein,while autophagosomes and synaptic ultrastructure were examined by transmission electron microscopy.To identify candidate therapeutics,protein-protein interaction analysis,molecular docking,and molecular dynamics simulations were performed.Pranlukast was selected for in vivo validation against stan-dard comparators(edaravone and nimodipine).RESULTS:MRTF-A overexpression significantly activated neuronal au-tophagy via the AKT/mTOR pathway(P<0.01)and preserved synaptic integrity,resulting in marked attenuation of cere-bral injury(P<0.01).PPI analysis identified β-actin,glyceraldehyde-3-phosphate dehydrogenase and glycogen synthase kinase-3β as core MRTF-A interactors.Pranlukast demonstrated strong predicted binding affinity for MRTF-A-associated targets.In vivo,pranlukast treatment significantly improved neurological outcomes(P<0.05),reduced infarct volume(P<0.01),and enhanced autophagy in the ischemic brain,preserving synaptic integrity(P<0.05 or P<0.01)in MCAO rats.Its efficacy was comparable to or exceeded that of edaravone and nimodipine.CONCLUSION:MRTF-A confers neuroprotection in cerebral ischemia-reperfusion injury by modulating AKT/mTOR-dependent autophagy and maintaining synaptic plasticity.Pranlukast,identified through structure-based drug screening,shows promising therapeutic potential as a novel MRTF-A-targeted intervention for ischemic stroke.关键词
脑缺血再灌注损伤/心肌素相关转录因子A/自噬/突触可塑性/虚拟筛选/普仑司特Key words
cerebral ischemia-reperfusion injury/myocardin-related transcription factor-A/autophagy/synap-tic plasticity/virtual screening/pranlukast分类
医药卫生引用本文复制引用
张添琦,张春艳,夏天骄,王碧洁,张希源,曾巧春,汪诗娆,曹晓璐,王江友..MRTF-A通过激活自噬减轻大鼠脑缺血再灌注后突触损伤的机制探寻与新药筛选[J].中国病理生理杂志,2026,42(1):1-12,12.基金项目
国家自然科学基金资助项目(No.81801307) （No.81801307）
武汉中青年医学骨干人才培养工程资助项目(第七批) （第七批）
职业危害识别与控制湖北省重点实验室开放基金项目(No.OHIC2022K01) （No.OHIC2022K01）
武汉亚心总医院科研创新基金资助(No.2022KYCX1-A01) （No.2022KYCX1-A01）
