Lipoxin A4 inhibits 5-lipoxygenase translocation and leukotrienes biosynthesis to exert a neuroprotective effect in cerebral ischemia/reperfusion injury.
Lipoxin A(4) (LXA(4)), a biologically active eicosanoid with anti-inflammatory and pro-resolution properties, was recently found to have neuroprotective effects in brain ischemia. As 5-lipoxygenase (5-LOX) and leukotrienes are generally considered to aggravate cerebral ischemia/reperfusion (I/R) injury, we investigated their effects on LXA(4)-mediated neuroprotection by studying middle cerebral artery occlusion (MCAO)/reperfusion in rats and oxygen-glucose deprivation (OGD)/recovery in neonatal rat astrocyte primary cultures. LXA(4) effectively reduced infarct volumes and brain edema, and improved neurological scores in the MCAO/reperfusion experiments; this effect was partially blocked by butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc2), a specific antagonist of the LXA(4) receptor (ALXR). Total 5-LOX expression did not change, regardless of treatment, but LXA(4) could inhibit nuclear translocation induced by MCAO or OGD. We also found that LXA(4) inhibits the upregulation of both leukotriene B(4) (LTB(4)) and leukotriene C(4) (LTC(4)) and the phosphorylation of extracellular signal-regulated kinase (ERK) induced by MCAO or OGD. The phosphorylation of the 38-kDa protein kinase (p38) and c-Jun N-terminal kinase (JNK) was not altered throughout the experiment. These results suggest that the neuroprotective effects of LXA(4) are probably achieved by anti-inflammatory mechanisms that are partly mediated by ALXR and through an ERK signal transduction pathway.
Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, No. 13, Hangkong Road, Wuhan, 430030, China.
Le
L
Wu
Sen
S
Miao
Lin-Bing
LB
Zou
Ping
P
Wu
Hua
H
Hao
Ke
K
Tang
Pan
P
Zeng
Jing
J
Xiong
Hong-Hua
HH
Li
Qiang
Q
Wu
Lei
L
Cai
Du-Yun
DY
Ye
D000818:Animals; D000831:Animals, Newborn; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000235:genetics / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis* / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D015289:Leukotrienes; D044045:Lipoxins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C040527:lipoxin A4; D007975:Leukotriene B4; D017997:Leukotriene C4; D001094:Arachidonate 5-Lipoxygenase; D005947:Glucose; D010100:Oxygen; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one