Lipoxin A4 methyl ester ameliorates cognitive deficits induced by chronic cerebral hypoperfusion through activating ERK/Nrf2 signaling pathway in rats

Lipoxin A(4) (LXA(4)) is known for its powerful anti-inflammatory function. Current studies in vitro suggest that LXA(4) possesses novel antioxidant effect. The aim of this study is to examine whether Lipoxin A(4) methyl ester (LXA(4) ME) has neuroprotective effects against chronic cerebral hypoperfusion, and if so, whether the effects of LXA(4) ME are associated with its potential antioxidant property. Adult male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) and randomly assigned into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, LXA(4) ME10 (BCCAO + LXA(4) ME 10 ng per day) group and LXA(4) ME100 (BCCAO + LXA(4) ME 100 ng per day) group. LXA(4) ME was administered through intracerebroventricular injection for 2 consecutive weeks. LXA4 ME significantly alleviated spatial learning and memory impairments, as assessed by Morris water maze and inhibited the loss of neurons in the CA1 region of the hippocampus. Biochemically, LXA4 ME phosphorylated extracellular signal regulated kinase (ERK) 1/2 and enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and its nuclear translocation, as well as NAD(P)H:quinone oxidoreductase 1 (NQO1) expression. LXA(4) ME reduced lipid peroxidative production in the hippocampus, as measured by immunohistochemical staining for 4-Hydroxynonenal (4-HNE). In addition, LXA(4) ME significantly elevated the ratio of Bcl-2/Bax and decreased cleaved caspase-3 expression in the hippocampus. Therefore, these data suggest that LXA(4) ME exerts beneficial effects on the cognitive impairment induced by chronic cerebral hypoperfusion through attenuating oxidative injury and reducing neuronal apoptosis in the hippocampus, which is most likely associated with the activation of ERK/Nrf2 signaling pathway. (C) 2014 Elsevier Inc. All rights reserved.