title: Tetramethylpyrazine-2'-O-sodium ferulate attenuates blood-brain barrier disruption and brain oedema after cerebral ischemia/reperfusion.
abstract: Disruption of blood-brain barrier (BBB) and subsequent oedema are major causes of the pathogenesis in ischaemic stroke with which the current clinical therapy remains unsatisfied. In this study, we examined the therapeutic effect of tetramethylpyrazine-2'-O-sodium ferulate (TSF)-a novel analogue of tetramethylpyrazine in alleviating BBB breakdown and brain oedema after cerebral ischaemia/reperfusion (I/R). Then, we explored the potential mechanism of the protection on BBB disruption in cerebral I/R rat models. Male Sprague-Dawley rats (250-300 g) were subjected to 120 min middle cerebral artery occlusion (MCAO), followed by 48 h reperfusion. TSF (10.8, 18 and 30 mg kg-1) and ozagrel (18 mg kg-1) were administrated by intravenous injection immediately for the first time and then received the same dose every 24 h for 2 days. We found that TSF treatment significantly attenuated the cerebral water content, infarction volume and improved neurological outcomes in MCAO rats compared to I/R models. Moreover, we investigated the effect of TSF on the BBB for that cerebral oedema is closely related to the permeability of the BBB. We found that the permeability of BBB was improved significantly in TSF groups compared to I/R model group by Evans blue leakage testing. Furthermore, the expressions of tight junction (TJ) proteins junction adhesion molecule-1 and occludin significantly decreased, but the protein expression of matrix metalloproteinase-9 (MMP-9) and aquaporin 4 (AQP4) increased after cerebral I/R, all of which were alleviated by TSF treatment. In conclusion, TSF significantly reduced BBB permeability and brain oedema, which were correlated with regulating the expression of TJ proteins, MMP-9 and AQP4. These findings provide a novel approach to the treatment of ischaemic stroke.
authors.affiliation: 1 Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: S-H
authors.initials: SH
authors.lastname: Xu
authors.affiliation: 2 School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China.|3 Institute of Materia Medica, Shandong Academy of Medical Sciences, Jinan, China.
authors.forename: M-S
authors.initials: MS
authors.lastname: Yin
authors.affiliation: 4 Eye Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: 1 Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: M-L
authors.initials: ML
authors.lastname: Chen
authors.affiliation: 5 Hefei Yigong Medicine Co., Ltd, Hefei, China.
authors.forename: G-W
authors.initials: GW
authors.lastname: He
authors.affiliation: 1 Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: P-P
authors.initials: PP
authors.lastname: Zhou
authors.affiliation: 1 Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Cui
authors.affiliation: 1 Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: 1 Department of Physiology, China Pharmaceutical University, Nanjing, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003373:Coumaric Acids / Q000494:pharmacology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D062793:Occludin / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D015815:Cell Adhesion Molecules; D003373:Coumaric Acids; C520495:F11r protein, rat; D018696:Neuroprotective Agents; D062793:Occludin; C568987:Ocln protein, rat; D011719:Pyrazines; C004999:ferulic acid; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; C017953:tetramethylpyrazine
keywords: Tetramethylpyrazine-2′-O-sodium ferulate; blood–brain barrier; ischaemia/reperfusion; oedema