RAGE-STAT3通路介导帕金森模型纹状体神经元线粒体损伤OA

[Objective]To investigate the molecular mechanisms by which the receptor for advanced glycation end products(RAGE)-signal transducer and activator of transcription 3(STAT3)signaling pathway mediates mitochondrial injury in striosome/matrix compartment neurons under dopaminergic depletion in Parkinson's disease(PD).[Methods]A 6-hydroxydopamine(6-OHDA)-induced rat model of PD was established and treated with the RAGE inhibitor FPS-ZM1.Immunohistochemistry,double immunofluorescence staining,transmission electron microscopy(TEM),Western blotting,and quantitative real-time PCR(qRT-PCR)were performed to evaluate RAGE and STAT3 expression as well as mitochondrial ultrastructure alterations in the striosome/matrix compartment.[Results]The density of RAGE-positive structures and the protein expression level of RAGE in the striosome/matrix compartment were significantly increased in PD rats compared with controls(P<0.05).Immunohistochemical and double immunofluorescence analyses demonstrated widespread STAT3 expression in striatal neurons,while the number of NeuN/STAT3 double-positive cells was significantly elevated in the PD group(P<0.05).Western blotting and qRT-PCR further confirmed significant upregulation of STAT3 protein and mRNA expression in PD rats(P<0.05).TEM analysis revealed marked mitochondrial abnormalities in PD neurons,including reduced mitochondrial density,enlarged mitochondrial area,decreased cristae number,cristae membrane disruption,and outer membrane damage(all P<0.05).Notably,FPS-ZM1 treatment partially reversed these mitochondrial ultrastructural alterations.[Conclusion]Activation of the RAGE-STAT3 signaling pathway contributes to mitochondrial structural disruption in striosome/matrix compartment neurons in PD.These findings suggest that the striosome/matrix compartment may represent a novel pathological target for investigating mitochondrial dysfunction and neurodegeneration in PD.