Lipoxin A4 inhibits 5-lipoxygenase translocation and leukotrienes biosynthesis to exert a neuroprotective effect in cerebral ischemia/reperfusion injury.

Abstract

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.

• Authors: Le Wu, Sen Miao, Lin-Bing Zou, Ping Wu, Hua Hao, Ke Tang, Pan Zeng, Jing Xiong, Hong-Hua Li, Qiang Wu, Lei Cai, Du-Yun Ye
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 48 Issue 1 Pg. 185-200 (Sep 2012) ISSN: 1559-1166 [Electronic] United States
• PMID: 22661361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• Leukotrienes
• Lipoxins
• Neuroprotective Agents
• RNA, Messenger
• lipoxin A4
• Leukotriene B4
• Leukotriene C4
• Arachidonate 5-Lipoxygenase
• Glucose
• Oxygen
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Animals, Newborn
• Arachidonate 5-Lipoxygenase (metabolism)
• Astrocytes (cytology, drug effects, metabolism)
• Brain Edema (drug therapy, metabolism, pathology)
• Brain Ischemia (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Glucose (pharmacology)
• Leukotriene B4 (metabolism)
• Leukotriene C4 (genetics, metabolism)
• Leukotrienes (biosynthesis, metabolism)
• Lipoxins (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Neuroprotective Agents (pharmacology)
• Oxygen (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, metabolism, pathology)