lipoxin-a4-methyl-ester and Cognition-Disorders

Since autophagy and endoplasmic reticulum stress mechanisms are involved in some neurodegenerative and cerebral vascular diseases, we suspected that similar mechanisms might participate in vascular cognitive impairments induced by chronic cerebral hypoperfusion. Lipoxin A4 methyl ester (LXA4 ME) is an inflammation inhibitor that exhibits potent protective effects in experimental stroke models. In an earlier study, we found that LXA4 ME improved cognitive deficit in a rat model of vascular cognitive impairment created using bilateral common carotid artery ligation (BCCAL) and two-vessel occlusion (2VO). In this study, LXA4 ME treatment of 2VO rats improved brain morphological defects. We found that LXA4 ME reduced the expression of some autophagy- and ERS-related factors in the hippocampus of 2VO rats, namely C/EBP homologous protein, beclin1 and the ratio of microtubule-associated protein light chain 3 II (LC3-II) to LC3-I. By contrast, LXA4 ME upregulated the protein expression of phospho-mTOR, total-mTOR, glucose-regulated protein 78 and spliced and unspliced X-box binding protein-1 mRNA. Differential protein regulation by LXA4 ME might underlie its ability to protect cognition after chronic cerebral hypoperfusion.

Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Blotting, Western; Carotid Artery, Common; Cerebrovascular Disorders; Cognition Disorders; DNA-Binding Proteins; Endoplasmic Reticulum Stress; Gene Expression; Hippocampus; Lipoxins; Male; Microtubule-Associated Proteins; Rats, Sprague-Dawley; Regulatory Factor X Transcription Factors; Reverse Transcriptase Polymerase Chain Reaction; TOR Serine-Threonine Kinases; Transcription Factors

Lipoxin A4 (LXA4) is known for its powerful anti-inflammatory function. Current studies in vitro suggest that LXA4 possesses novel antioxidant effect. The aim of this study is to examine whether Lipoxin A4 methyl ester (LXA4 ME) has neuroprotective effects against chronic cerebral hypoperfusion, and if so, whether the effects of LXA4 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, LXA4 ME10 (BCCAO+LXA4 ME 10 ng per day) group and LXA4 ME100 (BCCAO+LXA4 ME 100 ng per day) group. LXA4 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. quinone oxidoreductase 1 (NQO1) expression. LXA4 ME reduced lipid peroxidative production in the hippocampus, as measured by immunohistochemical staining for 4-Hydroxynonenal (4-HNE). In addition, LXA4 ME significantly elevated the ratio of Bcl-2/Bax and decreased cleaved caspase-3 expression in the hippocampus. Therefore, these data suggest that LXA4 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.

Topics: Animals; Cerebrovascular Circulation; Cognition Disorders; Extracellular Signal-Regulated MAP Kinases; Lipoxins; Male; Maze Learning; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Signal Transduction