Lipoxin A4 Inhibits 5-Lipoxygenase Translocation and Leukotrienes Biosynthesis to Exert a Neuroprotective Effect in Cerebral Ischemia/Reperfusion Injury

• Published in: Journal of molecular neuroscience 2012-09, Vol.48 (1), p.185-200
• Main Authors: Wu, Le, Miao, Sen, Zou, Lin-Bing, Wu, Ping, Hao, Hua, Tang, Ke, Zeng, Pan, Xiong, Jing, Li, Hong-Hua, Wu, Qiang, Cai, Lei, Ye, Du-Yun
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Arachidonate 5-Lipoxygenase - metabolism; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Biomedical and Life Sciences; Biomedicine; Brain Edema - drug therapy; Brain Edema - metabolism; Brain Edema - pathology; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cell Biology; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Glucose - pharmacology; Leukotriene B4 - metabolism; Leukotriene C4 - genetics; Leukotriene C4 - metabolism; Leukotrienes - biosynthesis; Leukotrienes - metabolism; Lipoxins - pharmacology; Male; MAP Kinase Signaling System - drug effects; Neurochemistry; Neurology; Neuroprotective Agents - pharmacology; Neurosciences; Oxygen - pharmacology; Proteomics; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; RNA, Messenger - metabolism
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-012-9807-4

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.