Lipoxin A sub(4) Inhibits 5-Lipoxygenase Translocation and Leukotrienes Biosynthesis to Exert a Neuroprotective Effect in Cerebral Ischemia/Reperfusion Injury

Lipoxin A sub(4) (LXA sub(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 sub(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 sub(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 sub(4) receptor (ALXR). Total 5-LOX expression did not change, regardless of treatment, but LXA sub(4) could inhibit nuclear translocation induced by MCAO or OGD. We also found that LXA sub(4) inhibits the upregulation of both leukotriene B sub(4) (LTB sub(4)) and leukotriene C sub(4) (LTC sub(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 sub(4) are probably achieved by anti-inflammatory mechanisms that are partly mediated by ALXR and through an ERK signal transduction pathway.