Neuroprotective effect of 2-hydroxy arachidonic acid in a rat model of transient middle cerebral artery occlusion.
Stroke modifies the composition of cell membranes by eliciting the breakdown of membrane phospholipids whose products, such as arachidonic acid (AA), are released in the cytosol. The action of enzymes such as cyclooxygenases on AA leads to inflammatory stimuli and increases the cell oxidative stress. We report here the neuroprotective effect of 2-hydroxyarachidonic acid (2OAA), a cyclooxygenase inhibitor derived from AA, as a promising neuroprotective therapy against stroke. The effect of a single dose of 2OAA, administered intragastrically 1h after the ischaemic insult, in a rat model of transient middle cerebral artery occlusion (tMCAO) was tested after 24h of reperfusion. Infarct volume was measured by TTC method to evaluate the neuroprotective effect. Levels of phospholipids and neutral lipids were measured by thin-layer chromatography. The expression of cPLA2 and sPLA2 phospholipases responsible for the cleavage of membrane phospholipids, as well as the expression of antioxidant enzymes, was measured by qPCR. Lipid peroxidation was measured as the concentration of malondialdehyde and 4-hydroxynonenal. The treatment with 2OAA reduced the infarct volume and prevented ischaemia-induced increases in transcription levels of free fatty acid (FFAs), as well as in both phospholipases A2 (cPLA2 and sPLA2). The lipid peroxidation and the transcription levels of antioxidant enzymes induced by ischaemia were also decreased by this treatment. We conclude that 2OAA treatment results in a strong neuroprotective effect that seems to rely on a decrease in PLA2 transcriptional activity. This would reduce their action on the membrane phospholipids reducing reactive oxygen and nitrogen species generated by FFAs. Based on the transcriptional activity of the antioxidant enzymes, we conclude that the treatment prevents oxidative stress rather than promoting the antioxidant response. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.
Cell Biology, Institute of Biomedicine, University of León, León, Spain. Electronic address: iferu@unileon.es.
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Ugidos
Cell Biology, Institute of Biomedicine, University of León, León, Spain. Electronic address: msantg@unileon.es.
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Santos-Galdiano
Cell Biology, Institute of Biomedicine, University of León, León, Spain. Electronic address: dperr@unileon.es.
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Pérez-Rodríguez
Cell Biology, Institute of Biomedicine, University of León, León, Spain. Electronic address: banus@unileon.es.
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Anuncibay-Soto
Cell Biology, Institute of Biomedicine, University of León, León, Spain. Electronic address: efonb@unileon.es.
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Font-Belmonte
Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Balearic Islands, Spain. Electronic address: david.lopez@uib.es.
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López
Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Balearic Islands, Spain. Electronic address: maitane.ibarguren@uib.es.
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Ibarguren
Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Balearic Islands, Spain. Electronic address: xavier.busquets@uib.es.
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Busquets
Cell Biology, Institute of Biomedicine, University of León, León, Spain. Electronic address: aferl@unileon.es.
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Fernández-López
D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D054467:Phospholipases A2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C000588452:2-hydroxyarachidonic acid; D001095:Arachidonic Acids; D018696:Neuroprotective Agents; D054467:Phospholipases A2
Cyclooxygenase 1; Cyclooxygenase 2; Free fatty acids; Oxidative stress; Phospholipase A2; tMCAO