title: Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat.
abstract: BACKGROUND
  In animal models, ischemia reperfusion (IR) injury triggers membrane lipid degradation and accumulation of lipoxidative exacerbations in neurovascular unit, leading to blood brain barrier (BBB) damage and neurologic deficits. In this study, we investigated whether impeding membrane lipid breakdown by inhibiting secretory phospholipase A2 (sPLA2) activity reduces BBB leakage, leading to neuroprotection and functional recovery.
  
  
  METHODS
  Focal cerebral IR injury was induced by middle cerebral artery occlusion (MCAO) in adult male rats. A sPLA2 inhibitor, 7,7-dimethyleicosadienoic acid (DEDA), was administered following IR injury. DEDA-treated animals were compared with vehicle-treated in terms of BBB leakage, edema, infarct volume, and neurological deficit. Membrane lipid degradation and the expression/activity of sPLA2 were also assessed. The role of one of the sPLA2 products, arachidonic acid (AA), on the morphology of the differentiated neuronal cell PC12 was examined by light microscopy.
  
  
  RESULTS
  Treatment with DEDA after IR injury not only reduced BBB leakage but also decreased infarct volume and improved neurologic function. The treatment attenuated both the activity of sPLA2 and the levels of sPLA2-derived oxidized products. The metabolites of lipid oxidation/peroxidation, including the protein carbonyl, were reduced as well. The treatment also restored the levels of glutathione, indicating attenuation of oxidative stress. In vitro treatment of PC12 cells with DEDA did not restore the AA-mediated inhibition of neurite formation and the levels of glutathione, indicating that effect of DEDA is up stream to AA release.
  
  
  CONCLUSIONS
  sPLA2-derived oxidative products contribute to significant neurovascular damage, and treatment with sPLA2 inhibitor DEDA ameliorates secondary injury by reducing exacerbations from lipoxidative stress.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA. hoda@musc.edu
authors.forename: Md Nasrul
authors.initials: MN
authors.lastname: Hoda
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.forename: Mushfiquddin
authors.initials: M
authors.lastname: Khan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D020520:Brain Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D008563:Membrane Lipids; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C059778:7,7-dimethyl-5,8-eicosadienoic acid; D054497:Phospholipases A2, Secretory
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