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OA

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.