title: A lipoxin A4 analog ameliorates blood-brain barrier dysfunction and reduces MMP-9 expression in a rat model of focal cerebral ischemia-reperfusion injury.
abstract: LXA(4) methyl ester (LXA(4)ME), a lipoxin A(4) analog, reduces ischemic insult in the rat models of transient or permanent cerebral ischemic injury. We investigated whether LXA(4)ME could ameliorate blood-brain barrier (BBB) dysfunction after stroke by reducing matrix metalloproteinase (MMP)-9 expression. Adult male rats were subjected to 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Brain infarctions were detected by triphenyltetrazolium chloride (TTC) staining. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Temporal expression of MMP-9 was determined by zymography and Western blot. The presence of tissue inhibitors of metalloproteinase-1 (TIMP-1) was also determined by Western blot in tissue protein sample. Brain edema and Evans Blue leakage were significantly reduced after stroke in the LXA(4)ME group and were associated with reduced brain infarct volumes. MMP-9 activity and expression were inhibited by LXA(4)ME after stroke. In addition, LXA(4)ME significantly increased TIMP-1 protein levels. Our results indicate that LXA(4)ME reduces brain injury by improving BBB function in a rat model of MCAO, and that a relationship exists between BBB permeability and MMP-9 expression following ischemic insult. Furthermore, these results suggest that LXA(4)ME-mediated reduction of MMP-9 following stroke are attributed to increased TIMP-1 expression.
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China. shang_you@126.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Peipei
authors.initials: P
authors.lastname: Guo
authors.forename: Xi-Hong
authors.initials: XH
authors.lastname: Ye
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Yuan
authors.forename: Shang-Long
authors.initials: SL
authors.lastname: Yao
authors.forename: You
authors.initials: Y
authors.lastname: Shang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D004195:Disease Models, Animal; D044045:Lipoxins / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000172:deficiency*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*
chemical_list: D044045:Lipoxins; C573617:lipoxin A4 methyl ester; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat