title: SMND-309, a novel derivative of salvianolic acid B, protects rat brains ischemia and reperfusion injury by targeting the JAK2/STAT3 pathway.
abstract: SMND-309 is a novel derivative of salvianolic acid B, and has shown protective effects against rat cortical neuron damage in vitro and in vivo. However the molecular mechanisms through which SMND-309 affords this protection are unclear. The present study aimed to investigate the mechanisms associated with the protective activities of SMND-309 in a cerebral ischemia and reperfusion injury rat model. In this study, we used AG490, a specific inhibitor of the signaling pathway involving the Janus Kinase 2 (JAK2)/Signal Transducers and Activators of Transcription 3 (STAT3) signaling molecules and suramin, a potent inhibitor of vascular endothelial growth factor (VEGF), to investigate the mechanisms of SMND-309. The cerebral ischemia and reperfusion injury model was induced by performing middle cerebral artery occlusion (MCAO) in the rats. SMND-309 mitigated the effects of ischemia and reperfusion injury on brain by decreasing the infract volume, improving neurological function, increasing the survival of neurons and promoting angiogenesis by increasing the levels of erythropoietin (EPO), erythropoietin receptor (EPOR), phosphorylated JAK2 (P-JAK2), phosphorylated STAT3 (P-STAT3), VEGF and VEGF receptor 2 (Flk-1) in the brain. Our results suggest that SMND-309 provides significant neuroprotective effects against cerebral ischemia and reperfusion injury. The mechanisms of this protection may be attributed to the increased VEGF expression occurring from the JAK2/STAT3 pathway, activated by the increased EPO/EPOR expression in the brain.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhu
authors.forename: Libo
authors.initials: L
authors.lastname: Zou
authors.forename: Jingwei
authors.initials: J
authors.lastname: Tian
authors.forename: Guangying
authors.initials: G
authors.lastname: Du
authors.forename: Yubai
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001572:Benzofurans / Q000737:chemistry*; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014867:Water / Q000378:metabolism; D053630:Depsides
chemical_list: D001572:Benzofurans; D002109:Caffeic Acids; D004921:Erythropoietin; D053614:Janus Kinase 2; D018696:Neuroprotective Agents; D010750:Phosphoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D014867:Water; C539487:2-(6-(2-carboxyvinyl)-2,3-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)acrylic acid; C076944:salvianolic acid B; D053630:Depsides
keywords: (2E)-2-{6-[(E)-2-carboxylvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid; Cerebral ischemia; Erythropoietin; Salvia miltiorrhiza; Salviolic acid derivative; Vascular endothelial growth factor