title: Neuroprotection by the kappa-opioid receptor agonist, BRL52537, is mediated via up-regulating phosphorylated signal transducer and activator of transcription-3 in cerebral ischemia/reperfusion injury in rats.
abstract: The purpose of this study was to investigate whether the kappa-opioid receptor (KOR) agonist, BRL52537, has a neuroprotective effect against cerebral ischemia/reperfusion (I/R) injury in rats and further explore the underlying mechanisms. Adult male Sprague-Dawley rats were randomly assigned into sham (group A), I/R (group B), BRL52537 (KOR agonist) + I/R (group C), nor-BNI (nor-binaltorphimine, KOR antagonist) + I/R (group D), AG490 (STAT3 phosphorylation inhibitor) + I/R (group E), dimethyl sulfoxide (DMSO, vehicle of AG490) + I/R (group F), and BRL52537 + AG490 +I/R (group G) groups. Cerebral I/R injury was induced by 10 min exposure to global ischemia (4-VO). Histopathological changes and neuronal apoptosis were evaluated with H&E staining and the TUNEL assay, respectively. Expression levels of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 and caspase-3 were determined with western blot analysis. Our results showed that BRL52537 protects against I/R injury-induced brain damage and inhibits neuronal apoptosis to a significant extent. Additionally, BRL52537 promoted up-regulation of p-STAT3 and a marked decrease in caspase-3 expression. Based on the collective findings, we propose that the KOR agonist, BRL52537, protects against cerebral I/R injury via a mechanism involving STAT3 signaling.
authors.affiliation: Department of Anaesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China.
authors.forename: Shudong
authors.initials: S
authors.lastname: Fang
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Junrui
authors.initials: J
authors.lastname: Lu
authors.forename: Yesen
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology; D053148:Caspase 3; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C454101:1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine; D018696:Neuroprotective Agents; D010880:Piperidines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053148:Caspase 3